Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer

Abstract

Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/− EGFR antibodies by next-generation sequencing (“tumor tissue” cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent “liquid biopsy” cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies.

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

“…Potential cetuximab/panitumumab resistance alterations in RAS/RAF wild-type tumors included alterations that impact antibody binding, bypass track activation, and alteration of downstream signaling cascade nodes-all well-established resistance mechanisms in cancer. Specifically, we observed EGFR EC domain mutations, which have been shown to disrupt antibody binding, and amplification of MET and FLT3, all of which have been associated with resistance to anti-EGFR therapy in CRC [19,[29][30][31][32]. Concurrent or compensatory ERBB2 amplification is a poor prognostic indicator independent of KRAS and ERBB2 mutations, and mediates resistance in a portion of anti-EGFRtreated patients [33,34].…”

Circulating tumor cells as a prognostic and predictive marker in gastrointestinal stromal tumors: a prospective study

“…Targeted therapies have improved the treatment and survival of cancer patients over the past decade [31, 32]. Imatinib mesylate is the standard first-line therapy of unresectable or metastatic GIST [33].…”

Broad detection of alterations predicted to confer lack of benefit from EGFR antibodies or sensitivity to targeted therapy in advanced colorectal cancer

“…Potential cetuximab/panitumumab resistance alterations in RAS/RAF wild-type tumors included alterations that impact antibody binding, bypass track activation, and alteration of downstream signaling cascade nodes-all well-established resistance mechanisms in cancer. Specifically, we observed EGFR EC domain mutations, which have been shown to disrupt antibody binding, and amplification of MET and FLT3, all of which have been associated with resistance to anti-EGFR therapy in CRC [19,[29][30][31][32]. Concurrent or compensatory ERBB2 amplification is a poor prognostic indicator independent of KRAS and ERBB2 mutations, and mediates resistance in a portion of anti-EGFRtreated patients [33,34].…”