Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

Abstract

The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS , NRAS, and BRAF and amplification of ERBB2 and MET drive primary ( de novo ) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.Signifi cance: Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their effi cacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted.

mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism

“…53,54 In line with the phospho-RTK array results, immunoprecipitated total c-MET was found to be less phosphorylated in autophagy-compromised cells compared to autophagy-proficient HCT-116 KRAS WT cells (Figure 3a). In contrast, phosphorylation levels of both IGF- (Figure 3d).…”

“…28 Unlike in CML, activating mutations of PI3K and KRAS oncogenes are present in a significant proportion of CRC patients and are associated with resistance to EGFR targeted therapy and tumour aggressiveness. 54,62 Constitutive PI3K signalling should inhibit autophagy via mTORC1 (ref 9 ), whereas KRAS mutations are predicted to either inhibit (via PI3K/mTORC1) or activate autophagy. 37 As a result, we first investigated whether EGFR targeted therapy could Cetuximab concentrations and LC3B levels were detected by immunoblotting.…”

“…Both EGFR and c-MET have been proposed to play tumourpromoting roles in CRC. [52][53][54][55][56] Although autophagy acts as a pro-survival mechanism upon nutrient deprivation in CRC, 57 it remains unclear whether its inhibition could potentiate RTK targeted therapy. …”

Detection of KRAS Mutations in Plasma DNA Using a fully Automated Rapid Detection System in Colorectal Cancer Patients

“…In addition, we confirmed that KRAS mutations were newly detected after acquired resistance to anti-EGFR antibody contained in chemotherapy, as other papers have reported. Since the first report of a patient with acquired resistance to cetuximab having newly detected KRAS mutation in cancer tissue, several papers have demonstrated acquired KRAS mutations, including mutations detected in plasma [8,10,11]. The mechanism of appearance of KRAS mutations after acquired resistance to anti-EGFR antibody has been assumed to be clonal selection from a minor population of pre-existing mutations or novel spontaneous mutations, but this mechanism has not been clarified.…”

“…In addition to the relationship with primary resistance, these mutations were also detected in patients who acquired resistance to anti-EGFR antibodies [8][9][10][11]. Mechanisms of acquired resistance to anti-EGFR antibodies include activation of an alternative pathway, such as MET/HGF or EGFR, or activation of RAS/RAF/MAPK mediated through the appearance of KRAS mutations [12][13][14].…”