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Advances and Challenges in Targeted Therapy for Colorectal Cancer: A Focus on Adenomatous Polyposis Coli and Kirsten Rat Sarcoma Virus Mutations

  • Rui-Hong Gong1,
  • Si-Bao Chen1,2,3,*  and
  • Guo-Qing Chen1,2,3,* 
 Author information
Journal of Translational Gastroenterology   2024;2(1):52-59

doi: 10.14218/JTG.2023.00063

Abstract

The global burden of colorectal cancer (CRC) is a pressing concern, with a substantial impact on public health. Despite advancements in understanding the molecular mechanisms of CRC development, challenges remain in translating this knowledge into effective clinical interventions. Key genetic mutations, notably in the adenomatous polyposis coli (APC) and Kirsten rat sarcoma virus (KRAS) genes, are central to CRC initiation and progression. Current CRC treatments include surgery and chemotherapy, often combined with targeted agents. However, resistance and heterogeneity within CRC patients limit the effectiveness of these therapies. Promisingly, research has focused on targeting APC and KRAS mutations for therapy. Small molecules inhibiting the Wnt pathway and antibodies targeting specific components are under investigation. Targeting KRAS itself is challenging due to its conserved structure, but disrupting its membrane interactions and subcellular localization are potential therapeutic strategies. To address the limitations of single-drug therapy, combination approaches are gaining traction. Combination therapy not only minimizes off-target effects but also tackles drug resistance and diverse genetic alterations within tumors. The intricate interplay of mutations and pathways in CRC necessitates multifaceted therapeutic strategies. Although progress has been made in understanding CRC genetics and developing targeted therapies, there is still work to be done to translate these insights into effective clinical treatments for CRC patients. This review provides crucial information for novel combination treatments for CRC.

Keywords

Colorectal cancer, Adenomatous polyposis coli, Kirsten rat sarcoma virus, Combination therapy, CRC treatment, Drug resistant

Introduction

Colorectal cancer (CRC) is a malignant tumor that originates in the colon or rectum. CRC is a significant global health concern, as demonstrated by statistics from 2020, where approximately 150,000 individuals worldwide received a CRC diagnosis, resulting in 53,200 fatalities.1 Among these patients, 17,930 individuals under the age of 50 were diagnosed with CRC, leading to 3,640 deaths in this age group.1 Gender differences are apparent, with CRC being more prevalent in males than in females, as evidenced by data from the World Health Organization database. Furthermore, variations in CRC incidence rates are evident globally. Countries such as Australia, New Zealand, Europe, and North America experience higher rates of the disease, while Africa and South-Central Asia exhibit lower rates (Global Burden of Disease Cancer Collaboration). These disparities may stem from factors such as dietary habits, environmental influences, and genetic variations.2 The rising trend of CRC incidence is particularly evident in China, where the burden on the healthcare system has been steadily increasing, especially in developed regions. A similar scenario has been observed in Hong Kong, where CRC remains a common form of cancer, as highlighted by 5,634 new cases reported in 2018. Furthermore, the mortality rate for males was 37 per 100,000, while for females, it was 22.2 per 100,000 (Centre for Health Protection 2020).

CRC is not solely attributed to a single genetic mutation; instead, it emerges from intricate molecular signaling pathways characterized by a complex interplay of mutations and disruptions. This process involves a gradual transition from adenoma to carcinoma and eventually to metastatic disease—a multistep journey driven by gene mutations and irregular pathways.3 Recent advances in genome-wide sequencing have unveiled a comprehensive array of nearly 80 mutated genes implicated in CRC. Notably, among these are adenomatous polyposis coli (APC), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), and p53.4 The APC gene mutation, occurring in 70–80% of CRC cases, plays a pivotal role within the Wnt/beta-catenin signaling pathway is significant.5 In addition to APC, another recurrently observed mutation involves the RAS gene family, especially KRAS, a commonly altered oncogene affecting 30–50% of CRC patients.6 The p53 gene, functioning as a tumor suppressor, influences the cell cycle, apoptosis, genetic stability, and angiogenesis control.7 While specific mutations initiate tumorigenesis, it is important to recognize that the progression and development of tumors involve the intricate interplay of multiple genes.8 Additionally, epigenetic factors such as DNA methylation, histone modifications, chromatin remodelers, and noncoding RNAs have emerged as significant contributors to the advancement and growth of CRC.9

This review explores APC and KRAS mutations in colorectal cancer, discusses prevailing treatment challenges, and outlines emerging combination therapies. We aim for this review to enhance comprehension of colorectal cancer’s mutational landscape and therapeutic strategies, thereby fostering research and implementation of innovative combination therapies.

APC mutations in CRC

The APC gene holds substantial importance as a frequently mutated tumor suppressor gene within CRC.10 Situated on chromosome 5q21-q22, this gene spans 8535 nucleotides and comprises 21 exons encoding a 310 kDa protein containing 2843 amino acids. A pivotal site for both germline and somatic mutations of APC lies within exon 15, encompassing 75% of the gene’s coding sequence.11 This finding is consistent with the central role of APC in governing the influence of the Wnt pathway on the proliferation and differentiation of gastrointestinal tract cells.12 Mechanistically, APC plays a pivotal role in inhibiting β-catenin/T-cell factor (TCF)-dependent transcription through complex breakdown. This process involves stimulating the phosphorylation and subsequent ubiquitin-dependent degradation of β-catenin.13 APC bolsters this degradation mechanism by promoting Axin multimerization and stabilizing the Axin complex.14 Additional regulatory mechanisms include reducing nuclear β-catenin levels through the promotion of β-catenin export, direct binding to β-catenin to impede TCF interactions,15 and facilitating C-terminal binding protein (CtBP)-mediated repression of Wnt-target genes through direct interaction with a repression complex.16,17 Alterations in APC result in the activation of β-catenin/TCF transcriptional activity due to β-catenin accumulation. This attenuation of CtBP-mediated inhibition within the repression complex leads to elevated levels of downstream targets, including cyclin D1 and c-myc. These factors significantly influence tumor cell proliferation, apoptosis, and cell cycle regulation (Fig. 1).18,19 Evidently, APC intricately interacts with critical signaling pathways and biological processes implicated in CRC development.10 Recent investigations have shown that restoring APC functionality can promote tumor regression and restore crypt homeostasis in CRC, suggesting that the Wnt pathway is a promising therapeutic target for CRC treatment.20

A schematic diagram showing the Wnt signaling pathway in normal colonic epithelial cells and colon cancer cells.
Fig. 1  A schematic diagram showing the Wnt signaling pathway in normal colonic epithelial cells and colon cancer cells.

APC, adenomatous polyposis coli; CBP, cAMP-response element binding protein; CIBP, calcium- and integrin-binding protein; CK, creatine kinase. CtBP, C-terminal binding protein; GRO, growth-regulated oncogene alpha; GSK, glycogen synthase kinase LRP5/6, low-density lipoprotein receptor-related protein (LRP)5 and 6; Tcf/Lef, T-cell factor/lymphoid enhancer factor.

KRAS mutation in CRC

KRAS is one of the most commonly mutated genes in human cancer and has significant implications for CRC treatment. Within this context, various forms of KRAS mutations have been categorized into three main groups based on the altered codon: G12 (mutations at codon 12), G13 (mutations at codon 13), and Q61 (mutations at codon 61).21 Notably, KRAS mutations are prevalent in approximately 30–50% of CRC cases.6 Among these mutations, 15 distinct point mutations are found to be particularly significant: G12A, G12D, G12F, G12K, G12N, G12S, G12V, G12Y, G12C, G12E, G12I, G12L, G12R, G12T, and G12W. Of these, G12D and G12V are the predominant subtypes, accounting for approximately 41% and 28%, respectively, of all G12 mutations.22 Clinical investigations consistently indicate that CRC patients carrying KRAS mutations tend to experience reduced survival rates compared to those without such mutations.23 Moreover, within the realm of KRAS mutations, G12D and G12V mutations have been associated with the poorest prognoses among CRC patients.24 Additionally, research findings demonstrate that individuals with G13 mutations in CRC patients experience significantly lower survival rates when diagnosed at stage I or II than when diagnosed with wild-type KRAS.6,25 Furthermore, for CRC patients harboring mutations at codon 12, the 5-year overall survival rate is notably lower than that for those carrying codon 13 mutations or wild-type KRAS.26

KRAS functions as a pivotal sensor that initiates a cascade of signaling molecules, facilitating the transmission of signals from the cell surface to the nucleus. This activation process significantly influences essential cellular functions, including cell differentiation, growth, chemotaxis, and apoptosis. Notably, KRAS plays a critical role in regulating key signaling pathways such as the PI3K-Akt and RAS-RAF-MAPK pathways, which play pivotal roles in cell proliferation.27–29 KRAS functions as a downstream component of the epidermal growth factor receptor (EGFR) pathway. Upon EGFR activation, the intracellular tyrosine kinase phosphorylates and activates KRAS, subsequently triggering the RAS-RAF-MAPK pathway. After activation, KRAS transitions to its activated state, KRAS-GTP, which is later hydrolyzed by GTPase, returning to the inactive KRAS-GDP state. This dynamic equilibrium involves alternating between its active (KRAS-GTP) and inactive (KRAS-GDP) forms. However, mutations within KRAS lead to the abnormal activation of downstream pathways, such as RAS-RAF-MAPK or phosphoinositide 3-kinase (PI3K), regardless of EGFR activation status (Fig. 2).30,31 Persistently active KRAS results in irregular and uncontrolled cell growth, cellular transformation, heightened cancer metastasis, and increased resistance to chemotherapy and EGFR-targeted therapies across various cancer types, including CRC.32,33

A schematic diagram showing oncogenic signaling pathways associated with mutated KRAS.
Fig. 2  A schematic diagram showing oncogenic signaling pathways associated with mutated KRAS.

ARAF, serine/threonine-protein kinase A-Raf; BRAF, B-Raf proto-oncogene, serine/threonine kinase; ERK, extracellular signal-regulated kinase; KRAS, Kirsten rat sarcoma 2 viral oncogene homolog; MEK, mitogen-activated protein kinase kinase; RAF1, rapidly accelerated fibrosarcoma 1.

Clinical challenges

Surgery stands as the primary curative approach for patients with nonmetastatic CRC, while chemotherapy offers an alternative therapeutic avenue. Notable drugs utilized for CRC treatment include 5-fluorouracil (5-FU), capecitabine, irinotecan, oxaliplatin, cetuximab, and panitumumab.34 In addition to conventional chemotherapy, targeted agents play a role in treating metastatic CRC. For example, cetuximab, the first FDA-approved targeted drug for CRC, targets EGFR. Additionally, bevacizumab, focusing on VEGF, has gained approval. Other drugs like panitumumab, regorafenib, and ramucirumab, all targeting VEGF/VEGFR, have also been approved for CRC treatment. Notably, recent years have seen the approval of immune checkpoint inhibitors such as pembrolizumab, nivolumab, and ipilimumab.35 However, the landscape of CRC is complex and characterized by multifaceted processes marked by a sequence of genetic alterations.36 Notably, the pronounced occurrence of tumor heterogeneity in CRC, stemming from chromosomal instability or microsatellite instability,37 collectively influences the efficacy of targeted therapies.

Despite these promising avenues, drugs specifically targeting APC and/or KRAS mutations have yet to receive FDA approval. CRC frequently involves APC and KRAS mutations, rendering them attractive therapeutic targets. However, it is important to note that medications aimed at targeting the APC/WNT/beta-catenin signaling pathways are currently in the preclinical development phase (Table 1).38,39–46

Table 1

Selected targeted therapy trials for colorectal cancer

TreatmentTrailSample sizeStudy groupsResponse rateSide effectsReference
WNT974Phase 194BRAF-mutant CRC, BRAF-mutant CRC with RNF43 mutation and/or RSPO fusionN.ADysgeusia, Decreased appetite, and Nausea39
ETC-1922159Phase 120Metastatic solid tumorsN.ADysgeusia, β-CTX increase, Fatigue, Constipation, and Nausea40
RXC004Phase 220RNF43 or RSPO aberrated, metastatic, microsatellite stable colorectal cancerOngoingOngoing41
CGX1321Phase 177colorectal cancer or small bowel cancer carrying RSPO or RNF43 alterationsN.ADysgeusia, Bone resorption42
OTSA101-DTPA-90YPhase 120Progressive advanced Synovial SarcomasN.AReversible hematological disorders43
OMP-18R5Phase 118Advanced solid tumorsN.AFatigue, Vomiting, Abdominal pain, Constipation, Diarrhea and Causea44
PRI-724Phase 118Advanced solid tumorsN.AHyperbilirubinemia, Diarrhea, Bilirubin elevation, Hypophosphatemia, Nausea, Fatigue, Anorexia, Thrombocytopenia and Alkaline phosphatase elevation.45
GDC-0623phase 145Advanced solid tumorsN.ARash, Gastrointestinal symptoms and Visual disturbance46

Over the past decade, a dedicated pursuit has aimed to advance therapeutic strategies against the APC/WNT/beta-catenin signaling pathway in CRC patients. This endeavor has led to the discovery of a range of small molecules that effectively inhibit this pathway by targeting various signaling molecules.38,47,48 Notably, phase 1 and 2 clinical trials have been conducted for these inhibitors, including WNT974, ETC-1922159, RXC004, and CGX1321, which are PORCN inhibitors; OTSA101-DTPA-90Y, which functions as an FZD10 antagonist; OMP-18R5, a monoclonal antibody targeting FZD receptors; and PRI-724, a CEB/beta-catenin antagonist.49 Despite these promising efforts, none have yet secured FDA approval for CRC treatment. The exceptional complexity of the APC/WNT/beta-catenin pathway plays a significant role in this process. Beyond APC mutations, beta-catenin can be further activated through alternate signaling pathways.50–53 Numerous studies suggest that these supplementary regulatory processes contribute to the observed limitations in achieving satisfactory clinical outcomes with these inhibitors and antibodies. Moreover, the potential toxicity of these inhibitors on the intestinal epithelium, coupled with the risk of off-target effects, might have hindered their progress in clinical applications (Table 2).54

Table 2

Hurdles of development of targeted therapies

TargetObstacles
APCPotential toxicity; Off-target effects.
KRASHighly conserved nature of the GTPase; Catalytic domain on KRAS proteins; Competitive binding issues; Limited binding sites.

Presently, there is a lack of approved drugs specifically targeting KRAS for CRC treatment. Instead, approvals have been directed toward inhibitors of downstream signaling cascades, such as the RAF and MEK pathways (Table 1).55 For example, selumetinib (AZD6244), functioning as a MEK 1/2 inhibitor, is designed to hinder the MEK enzyme within the RAS/MAPK pathway. Additionally, trametinib, a potent and selective ATP-independent inhibitor of MEK1/2 kinases, falls within this category.56 Another example is GDC-0623, a MEK inhibitor that enhances BIM expression, which is currently under investigation in a phase I clinical trial.57 However, concentrating solely on downstream cascades unrelated to KRAS may not yield the desired effectiveness in cancer treatment. This challenge might arise from the inherent difficulty in pharmaceutically targeting KRAS.58 Research has highlighted several obstacles in the quest for KRAS-targeted treatments (Table 2). These include the highly conserved nature of the GTPase catalytic domain on KRAS proteins, the competitive binding issues faced by small molecule drugs with substrates, and the limited number of binding sites on the KRAS protein surface for small molecule inhibitors.59–64 Nevertheless, strategies aimed at disrupting KRAS-membrane interactions and altering KRAS subcellular localization continue to hold promise. Recent insights into functionally significant posttranslational modifications of the KRAS protein, including phosphorylation and ubiquitylation, introduce novel prospects for inhibiting KRAS activity.

Development of novel drug combinations for CRC treatment

The inception of combination therapy dates back to 1965 when Emil Frei and colleagues pioneered the inaugural utilization of combination chemotherapy in pediatric patients afflicted with acute leukemia.65 The resounding success of this innovative therapeutic paradigm ushered in a transformative era within clinical oncology.66 Subsequently, cancer research has increasingly focused on the exploration of combination therapies designed to concurrently target disparate molecular pathways, resulting in favorable anticancer outcomes. Concurrently, progress in cancer cell genomics, epigenomics, transcriptomics, and proteomics has facilitated the identification of novel molecular targets, underpinning the development of highly selective targeted anticancer interventions.67 These targeted therapies have substantially diversified the arsenal of combinational anticancer modalities, capable of integration with other targeted therapies or conventional chemotherapeutic agents.68

The efficacy of single-drug therapy often encounters limitations, leading to the emergence of drug resistance.69 In fact, resistance to 5-FU treatment occurs in approximately half of all CRC patients.70 Recently, there has been a growing focus on combining drugs to leverage synergistic interactions. Combination therapy offers notable advantages. First, it allows for reduced drug dosages, thereby decreasing the risk of off-target side effects.71 Second, this approach targets multiple facets, effectively curbing the development of drug resistance.72 These attributes hold particular importance when addressing heterogeneous cancers such as CRC.73 The intrinsic heterogeneity of CRC is well documented. In some cases, patients with the same tumor may display distinct genetic alterations, and even cells within a tumor might carry varying genetic mutations. Resistance to a single chemotherapeutic agent, whether innate or acquired, can stem from factors such as suppressed apoptosis or enhanced DNA repair, leading to cancer relapse or treatment resistance. Therefore, combination therapy is especially advantageous because diverse drugs can target different pathways or genes. This approach substantially reduces the number of cancer cells that can withstand treatment, effectively delaying cancer recurrence and, optimally, achieving complete eradication.

The utilization of combination chemotherapy has evolved into the prevailing standard of care within the field of medical oncology. Considering the profusion of available chemotherapeutic and targeted anticancer agents, forecasting and developing innovative drug combinations presents a formidable challenge. Thus, it is imperative to explore the requisite methodologies for prognosticating combinations that exhibit synergistic anticancer efficacy.

Conclusion

CRC represents a significant global health challenge, with considerable variations in incidence rates across regions and gender differences. Among numerous genes that contribute to CRC development, APC and KRAS mutations are pivotal factors driving tumorigenesis. Current research efforts are focused on inhibiting the APC/Wnt/beta-catenin and KRAS pathways. While progress has been made in the field of small molecules and inhibitors, their clinical application has encountered hurdles due to the complexity of these pathways and the emergence of alternative signaling mechanisms. Combination therapy has emerged as a promising approach to address the complexity and heterogeneity of CRC. By targeting multiple facets and pathways simultaneously, combination therapies can potentially enhance treatment efficacy, mitigate drug resistance, and ultimately improve patient outcomes.

Abbreviations

5-FU: 

5-fluorouracil

APC: 

adenomatous polyposis coli

CEB: 

CCAAT enhancer binding protein

CRC: 

colorectal cancer

CtBP: 

C-terminal binding protein

EGFR: 

growth factor receptor

FZD: 

frizzled receptors

GDP: 

guanosine diphosphate

GTP: 

guanosine triphosphate

KRAS: 

Kirsten rat sarcoma 2 viral oncogene homolog

MAPK: 

mitogen-activated protein kinase

MEK: 

mitogen-activated protein kinase kinase

PI3K: 

phosphatidylinositol 3-kinase

PORCN: 

porcupine O-Acyltransferase

RAF: 

rapidly accelerated fibrosarcoma

RAS: 

rat sarcoma

TCF: 

T-cell factor

VEGF: 

vascular endothelial growth factor

VEGFR: 

vascular endothelial growth factor receptor

WNT: 

wingless-related integration site

Declarations

Acknowledgement

None.

Funding

None.

Conflict of interest

All authors declared that there are no conflict of interests.

Authors’ contributions

Conceptualization (GQC, SC, RHG), Data curation and original draft preparation (RHG, GQC, SC), Figures and Tables (RHG, GQC, SC), Review and editing (GQC, SC, RHG). All authors contributed to the article and approved the final manuscript.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin 2021;71(1):7-33 View Article PubMed/NCBI
  2. Song M, Chan AT, Sun J. Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer. Gastroenterology 2020;158(2):322-340 View Article PubMed/NCBI
  3. Wu Z, Li Y, Zhang Y, Hu H, Wu T, Liu S, et al. Colorectal Cancer Screening Methods and Molecular Markers for Early Detection. Technol Cancer Res Treat 2020;19:1533033820980426 View Article PubMed/NCBI
  4. Dunne PD, Arends MJ. Molecular pathological classification of colorectal cancer-an update. Virchows Arch 2024;484(2):273-285 View Article PubMed/NCBI
  5. Hankey W, Frankel WL, Groden J. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting. Cancer Metastasis Rev 2018;37(1):159-172 View Article PubMed/NCBI
  6. Zhu G, Pei L, Xia H, Tang Q, Bi F. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer 2021;20(1):143 View Article PubMed/NCBI
  7. Liebl MC, Hofmann TG. The Role of p53 Signaling in Colorectal Cancer. Cancers (Basel) 2021;13(9):2125 View Article PubMed/NCBI
  8. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science 2013;339(6127):1546-1558 View Article PubMed/NCBI
  9. Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol 2020;17(2):111-130 View Article PubMed/NCBI
  10. Kok SY, Nakayama M, Morita A, Oshima H, Oshima M. Genetic and nongenetic mechanisms for colorectal cancer evolution. Cancer Sci 2023;114(9):3478-3486 View Article PubMed/NCBI
  11. Béroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res 1996;24(1):121-4 View Article PubMed/NCBI
  12. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther 2022;7(1):3 View Article PubMed/NCBI
  13. Rubinfeld B, Albert I, Porfiri E, Fiol C, Munemitsu S, Polakis P, et al. Binding of GSK3beta to the APC-beta-catenin complex and regulation of complex assembly. Science 1996;272(5264):1023-1026 View Article PubMed/NCBI
  14. Pronobis MI, Rusan NM, Peifer M. A novel GSK3-regulated APC:Axin interaction regulates Wnt signaling by driving a catalytic cycle of efficient βcatenin destruction. Elife 2015;4:e08022 View Article PubMed/NCBI
  15. Neufeld KL, Zhang F, Cullen BR, White RL. APC-mediated downregulation of beta-catenin activity involves nuclear sequestration and nuclear export. EMBO Rep 2000;1(6):519-23 View Article PubMed/NCBI
  16. Hamada F, Bienz M. The APC tumor suppressor binds to C-terminal binding protein to divert nuclear beta-catenin from TCF. Dev Cell 2004;7(5):677-85 View Article PubMed/NCBI
  17. Sierra J, Yoshida T, Joazeiro CA, Jones KA. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev 2006;20(5):586-600 View Article PubMed/NCBI
  18. He TC, Sparks AB, Rago C, Hermeking H, Zawel L. Identification of c-MYC as a target of the APC pathway. Science 1998;281(5382):1509-1512 View Article PubMed/NCBI
  19. Yan H, Jiang F, Yang J. Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis. Genet Res (Camb) 2022;2022:5338956 View Article PubMed/NCBI
  20. Dow LE, O’Rourke KP, Simon J, Tschaharganeh DF, van Es JH, Clevers H, et al. Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer. Cell 2015;161(7):1539-1552 View Article PubMed/NCBI
  21. Uprety D, Adjei AA. KRAS: From undruggable to a druggable Cancer Target. Cancer Treat Rev 2020;89:102070 View Article PubMed/NCBI
  22. Christensen JG, Olson P, Briere T, Wiel C, Bergo MO. Targeting Krasg12c -mutant cancer with a mutation-specific inhibitor. J Intern Med 2020;288(2):183-191 View Article PubMed/NCBI
  23. Pang XL, Li QX, Ma ZP, Shi Y, Ma YQ, Li XX, et al. Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and KRAS mutation. Onco Targets Ther 2017;10:2645-2654 View Article PubMed/NCBI
  24. Li W, Liu Y, Cai S, Yang C, Lin Z, Zhou L, et al. Not all mutations of KRAS predict poor prognosis in patients with colorectal cancer. Int J Clin Exp Pathol 2019;12(3):957-967 PubMed/NCBI
  25. Chen J, Guo F, Shi X, Zhang L, Zhang A, Jin H, et al. BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients. BMC Cancer 2014;14:802 View Article PubMed/NCBI
  26. Abubaker J, Bavi P, Al-Haqawi W, Sultana M, Al-Harbi S, et al. Prognostic significance of alterations in KRAS isoforms KRAS-4A/4B and KRAS mutations in colorectal carcinoma. J Pathol 2009;219(4):435-445 View Article PubMed/NCBI
  27. Yoshizawa A, Sumiyoshi S, Sonobe M, Kobayashi M, Fujimoto M, Kawakami F, et al. Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients. J Thorac Oncol 2013;8(1):52-61 View Article PubMed/NCBI
  28. Degirmenci U, Wang M, Hu J. Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy. Cells 2020;9(1):198 View Article PubMed/NCBI
  29. Castellano E, Sheridan C, Thin MZ, Nye E, Spencer-Dene B. Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance. Cancer Cell 2013;24(5):617-630 View Article PubMed/NCBI
  30. Martelli V, Pastorino A, Sobrero AF. Prognostic and predictive molecular biomarkers in advanced colorectal cancer. Pharmacol Ther 2022;236:108239 View Article PubMed/NCBI
  31. Domagała P, Hybiak J, Sulżyc-Bielicka V, Cybulski C, Ryś J, Domagała W, et al. KRAS mutation testing in colorectal cancer as an example of the pathologist’s role in personalized targeted therapy: a practical approach. Pol J Pathol 2012;63(3):145-64 View Article PubMed/NCBI
  32. Shingu T, Holmes L, Henry V, Wang Q, Latha K, Gururaj AE, et al. Suppression of RAF/MEK or PI3K synergizes cytotoxicity of receptor tyrosine kinase inhibitors in glioma tumor-initiating cells. J Transl Med 2016;14:46 View Article PubMed/NCBI
  33. Van Schaeybroeck S, Kalimutho M, Dunne PD, Carson R, Allen W, Jithesh PV, et al. ADAM17-dependent c-MET-STAT3 signaling mediates resistance to MEK inhibitors in KRAS mutant colorectal cancer. Cell Rep 2014;7(6):1940-1955 View Article PubMed/NCBI
  34. Nussinov R, Tsai CJ, Jang H. Anticancer drug resistance: An update and perspective. Drug Resist Updat 2021;59:100796 View Article PubMed/NCBI
  35. Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 2020;5(1):22 View Article PubMed/NCBI
  36. Lahouel K, Younes L, Danilova L, Giardiello FM, Hruban RH, Groopman J, et al. Revisiting the tumorigenesis timeline with a data-driven generative model. Proc Natl Acad Sci USA 2020;117(2):857-864 View Article PubMed/NCBI
  37. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 2010;138(6):2059-72 View Article PubMed/NCBI
  38. Zhao H, Ming T, Tang S, Ren S, Yang H, Liu M, et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Mol Cancer 2022;21(1):144 View Article PubMed/NCBI
  39. Rodon J, Argilés G, Connolly RM, Vaishampayan U, de Jonge M, Garralda E, et al. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br J Cancer 2021;125(1):28-37 View Article PubMed/NCBI
  40. Tan SP, Matthew CH, Ng VS, Wells AM, John HS, Veronica D, et al. A phase 1B dose escalation study of ETC-159 in combination with pembrolizumab in advanced or metastatic solid tumours. J Clin Oncol 2023;41(suppl):2601-2601 View Article
  41. Kopetz S, Morris VK, O’Neil B, Bridgewater JA, Graham J, Parkes EE, et al. A multi-arm, phase 2, open-label study to assess the efficacy of RXC004 as monotherapy and in combination with nivolumab in patients with ring finger protein 43 (RNF43) or R-spondin (RSPO) aberrated, metastatic, microsatellite stable colorectal cancer following standard treatments. J Clin Oncol 2022;40(suppl):TPS3637-TPS3637 View Article
  42. Giannakis M, Le DT, Pishvaian MJ, Weinberg BA, Papadopoulos KP, Shen L, et al. Phase 1 study of WNT pathway Porcupine inhibitor CGX1321 and phase 1b study of CGX1321 + pembrolizumab (pembro) in patients (pts) with advanced gastrointestinal (GI) tumors. J Clin Oncol 2023;41(suppl):3514 View Article
  43. Giraudet AL, Cassier PA, Iwao-Fukukawa C, Garin G, Badel JN, Kryza D, et al. A first-in-human study investigating biodistribution, safety and recommended dose of a new radiolabeled MAb targeting FZD10 in metastatic synovial sarcoma patients. BMC Cancer 2018;18(1):646 View Article PubMed/NCBI
  44. Smith DC, Rosen LS, Chugh R, Goldman JW, Xu L, Kapoun A, et al. First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. J Clin Oncol 2013;31(suppl):2540 View Article
  45. El-Khoueiry AB, Ning Y, Yang D, Cole S, Kahn M, Zoghbi M, et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J Clin Oncol 2013;31(suppl):2501 View Article
  46. El-Khoueiry A, Kurkjian C, Semrad T, Musib L, Gates M, Eppler S, et al. A first in-human phase I study to evaluate the MEK1/2 inhibitor GDC-0623 in patients with advanced solid tumors. Mol Cancer Ther 2013;12(Suppl.11):B75 View Article
  47. Huang SM, Temple R, Throckmorton DC, Lesko LJ. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther 2007;81(2):298-304 View Article PubMed/NCBI
  48. Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, et al. Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α. Nat Chem Biol 2010;6(11):829-836 View Article PubMed/NCBI
  49. Jung YS, Park JI. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med 2020;52(2):183-191 View Article PubMed/NCBI
  50. Jung YS, Wang W, Jun S, Zhang J, Srivastava M, Kim MJ, et al. Deregulation of CRAD-controlled cytoskeleton initiates mucinous colorectal cancer via β-catenin. Nat Cell Biol 2018;20(11):1303-1314 View Article PubMed/NCBI
  51. Voloshanenko O, Erdmann G, Dubash TD, Augustin I, Metzig M, Moffa G, et al. Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nat Commun 2013;4:2610 View Article PubMed/NCBI
  52. Hao HX, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 2012;485(7397):195-200 View Article PubMed/NCBI
  53. Horst D, Chen J, Morikawa T, Ogino S, Kirchner T, Shivdasani RA, et al. Differential WNT activity in colorectal cancer confers limited tumorigenic potential and is regulated by MAPK signaling. Cancer Res 2012;72(6):1547-56 View Article PubMed/NCBI
  54. Kahn M. Can we safely target the WNT pathway?. Nat Rev Drug Discov 2014;13(7):513-32 View Article PubMed/NCBI
  55. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged?. Nat Rev Drug Discov 2020;19(8):533-552 View Article PubMed/NCBI
  56. Cheng Y, Tian H. Current Development Status of MEK Inhibitors. Molecules 2017;22(10):1551 View Article PubMed/NCBI
  57. Zaanan A, Okamoto K, Kawakami H, Khazaie K, Huang S, Sinicrope FA. The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism. J Biol Chem 2015;290(39):23838-23849 View Article PubMed/NCBI
  58. Khan I, Rhett JM, O’Bryan JP. Therapeutic targeting of RAS: New hope for drugging the “undruggable”. Biochim Biophys Acta Mol Cell Res 2020;1867(2):118570 View Article PubMed/NCBI
  59. Zimmerli D, Cecconi V, Valenta T, Hausmann G, Cantù C, Restivo G, et al. WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma. Oncogene 2018;37(27):3753-3762 View Article PubMed/NCBI
  60. Li H, Jiao S, Li X, Banu H, Hamal S, Wang X. Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/β-catenin signaling. Biochem Biophys Res Commun 2015;467(1):14-20 View Article PubMed/NCBI
  61. Kahlert UD, Suwala AK, Koch K, Natsumeda M, Orr BA, Hayashi M, et al. Pharmacologic Wnt Inhibition Reduces Proliferation, Survival, and Clonogenicity of Glioblastoma Cells. J Neuropathol Exp Neurol 2015;74(9):889-900 View Article PubMed/NCBI
  62. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible?. Nat Rev Drug Discov 2014;13(11):828-851 View Article PubMed/NCBI
  63. Ledford H. Cancer studies clash over mechanisms of malignancy. Nature 2015;528(7582):317 View Article PubMed/NCBI
  64. Lu SSM, Mohammed Z, Häggström C, Myte R, Lindquist E, Gylfe Å, et al. Antibiotics Use and Subsequent Risk of Colorectal Cancer: A Swedish Nationwide Population-Based Study. J Natl Cancer Inst 2022;114(1):38-46 View Article PubMed/NCBI
  65. Frei E, Karon M, Levin RH, Freireich EJ, Taylor RJ, Hananian J, et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 1965;26(5):642-656 PubMed/NCBI
  66. Ismail M, Khan S, Khan F, Noor S, Sajid H, Yar S, et al. Prevalence and significance of potential drug-drug interactions among cancer patients receiving chemotherapy. BMC Cancer 2020;20(1):335 View Article PubMed/NCBI
  67. Falzone L, Salomone S, Libra M. Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium. Front Pharmacol 2018;9:1300 View Article PubMed/NCBI
  68. Gilad Y, Gellerman G, Lonard DM, O’Malley BW. Drug Combination in Cancer Treatment-From Cocktails to Conjugated Combinations. Cancers (Basel) 2021;13(4):669 View Article PubMed/NCBI
  69. Huang L, Hu C, Di Benedetto M, Varin R, Liu J, Wang L, et al. Induction of multiple drug resistance in HMEC-1 endothelial cells after long-term exposure to sunitinib. Onco Targets Ther 2014;7:2249-2255 View Article PubMed/NCBI
  70. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355(9209):1041-1047 View Article PubMed/NCBI
  71. Mokhtari RB, Qorri B, Baluch N, Sparaneo A, Fabrizio FP, Muscarella LA, et al. Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis. Oncotarget 2021;12(15):1470-1489 View Article PubMed/NCBI
  72. Saputra EC, Huang L, Chen Y, Tucker-Kellogg L. Combination Therapy and the Evolution of Resistance: The Theoretical Merits of Synergism and Antagonism in Cancer. Cancer Res 2018;78(9):2419-2431 View Article PubMed/NCBI
  73. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature 2013;501(7467):328-337 View Article PubMed/NCBI
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Advances and Challenges in Targeted Therapy for Colorectal Cancer: A Focus on Adenomatous Polyposis Coli and Kirsten Rat Sarcoma Virus Mutations

Rui-Hong Gong, Si-Bao Chen, Guo-Qing Chen
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