The genomic landscape of response to EGFR blockade in colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer world-wide with 1.2 million patients diagnosed yearly. In late stage CRC, the most commonly used targeted therapies are monoclonal antibodies cetuximab and panitumumab, which inactivate EGFR1. Recent studies have identified alterations in KRAS2–4 and other genes5–13 as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in CRC and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in CRC on response to anti-EGFR antibody therapy, we performed complete exome sequence and copy number analyses of 129 patient-derived tumorgrafts and targeted genomic analyses of 55 patient tumors, all of which were KRAS wild-type. We analyzed the response of tumors to anti-EGFR antibody blockade in tumorgraft models or in clinical settings. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and provide new avenues for intervention in the management of CRC.

Targeting the HER family with Pan-HER effectively overcomes resistance to cetuximab

“…It has been exhibited that cetuximab-resistant clones have increased not only EGFR, HER2, HER3, and HER4, but also other receptor tyrosine kinases (RTKs) such as cMET, AXL, and IGF1R (13,45,46). Recently, mutations in the genes encoding other RTKs, such as FGFR1 or PDGFRA were found in CRC PDX models with intrinsic resistance to cetuximab (47). Nakamura et al also found HER4 mutation in cetuximabresistant ESCC or HNSCC cells (48).…”

S3-Leitlinie – Kolorektales Karzinom

“…Allerdings liegen erste Daten vor, welche darauf hinweisen, dass eine HER2-neu Amplifikation mit einer Resistenz gegen anti-EGFR Substanzen verbunden sein kann [1070,1071]. Darüber hinaus zeigt die HERACLES Studie, dass Patienten mit RAS-wt mKRK, die gegen eine Standardtherapie (einschließlich Cetuximab oder Panitumumab) refraktär waren und eine HER2 Amlifikation/Überexpression aufwiesen, von einer Behandlung mit Trastuzumab plus Lapatinib profitierten [1072] (siehe 9.8.6).…”

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

“…Smaller studies have suggested that RAS amplification and alterations in genes, including PIK3CA, EGFR, and ERBB2, are associated with resistance to cetuximab or panitumumab in CRC, but a large comprehensive study reporting the incidence and diversity of these alterations is lacking [18][19][20][21]. Furthermore, assessment of the genomic landscape of CRC has used mainly treatment-naïve, largely nonmetastatic primary tumors or focused assessments of specimens from patients with advanced disease [22,23]. We present the genomic profiles and clinical implications of 4,422 CRC cases assayed in the course of clinical care, often in the setting of metastatic disease.…”