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Citation: Hang KC. Resistance to Anti-EGFR targeted therapy mediated by oncogenetic mutations in colorectal cancer: Revision of

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Editorial

Resistance to anti-EGFR targeted therapy mediated by oncogenetic

mutations in colorectal cancer: Revision of the dogma?

Dr. Kan Chi Hang

簡志恒

Histopathology Laboratory, St. Teresa’s Hospital, Hong Kong SAR, China.

Traditionally, systemic treatment for high stage colorectal carcinoma (CRC) is mainly fluorouracil-based

chemotherapy [1]. The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, by acting on

specific molecular pathways in tumor growth or modulating immune response towards tumor cells, provide

a more targeted response, a better side effect profile and greater impact on patient survival compared with

conventional molecules. This monoclonal antibody that binds the extracellular domain of epidermal growth

factor receptor, is known to be effective only in a subset of KRAS wild-type colorectal cancers.

Patients with mutations in either KRAS or NRAS gene are not eligible for anti-EGFR monoclonal antibody

therapy [3]. This is due to downstream activation of the Ras/Raf/MAPK pathway by mutated RAS protein,

leading to cell proliferation which cannot be sufficiently inhibited by anti-EGFR receptor monoclonal

antibodies [4]. With the increasing choices of targeted agents, more and more biomarkers are tested.

Currently, the standard recommended biomarker panel for colorectal carcinoma would include KRAS, NRAS,

BRAF gene hotspot mutation detection and microsatellite instability test [5].

With the advances in genomic profiling and sequencing and the understanding of the resistance

mechanisms, the contraindication of anti-EGFR therapy in mutant KRAS patients may be revised.

Based on the fact that the KRAS mutation in CRC suppresses the phosphorylation of the AMP-activated

protein kinase (AMPK) known to be toxic for the tumor cells, Hua et al obtained a satisfactory response to

for the anti-EGFR antibodies in mutant KRAS CRC xenograft models after reactivation of the AMPK [6].

Knickelbein et al demonstrated that the anti-EGFR antibodies induce the death of CRC cells via a p73-

dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein (PUMA). This action is

abolished in case of KRAS mutation. These authors admitted that the restoration of this pathway by

inhibiting aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated

resistance to anti-EGFR antibodies [7]. In fifty-one CRC patient-derived xenografts study, Lee et al showed

that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared

with wild-type KRAS. The use of an anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-

affinity EGFR ligand enhanced CRC KRAS mutant cells cytotoxicity [8].

Dealing with the resistance to targeted therapies in CRC patient looks feasible. It could allow to broaden

the indications of anti-EGFR therapy and provide a better survival for a larger group of CRC patients. In this

era of precision and personalized medicine, a complete case specific tumor profiling and the comprehensive

study of the tumorogenesis mechanisms should allow to overcome the intrinsic and acquired resistance to

these targeted high effective therapies.

References

[1] Gill S, Loprinzi CL, Sargent DJ, Thomé SD, Alberts SR, Haller DG, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?

J Clin Oncol. 2004; 22:1797-806.

[2] Wu C. Systemic Therapy for Colon Cancer. Surg Oncol Clin N Am. 2018; 27:235-42.

[3] Piawah S, Venook AP. Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of

metastatic colorectal cancer. Cancer. 2019; 125:4139-47.

[4] Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006; 66:3992-5.

[5] Sepulveda AR, Hamilton SR, Allegra CJ, Grody W, Cushman-Vokoun AM, Funkhouser WK, et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline From the American

Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017; 35:1453-86.

[6] Ye H, Liu Y, Wu K, Luo H, Cui L. AMPK activation overcomes anti-EGFR antibody resistance induced by KRAS mutation in colorectal cancer. Cell Commun Signal. 2020; 18:115.

[7] Knickelbein K, Tong J, Chen D, Wang YJ, Misale S, Bardelli A, et al. Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. Oncogene.

2018; 37:4599-610.

[8] Lee HW, Son E, Lee K, Lee Y, Kim Y, Lee JC, et al. Promising therapeutic efficacy of GC1118, an anti-EGFR antibody, against KRAS mutation-driven colorectal cancer patient-derived xenografts.

Int J Mol Sci. 2019; 20:5894.