Transcriptional upregulation of HER2 expression in the absence of HER2 gene amplification results in cetuximab resistance that is reversed by trastuzumab treatment

Abstract

Abstract. The recent identification of HER2 gene amplification as a novel predictor of resistance to the EGFR (HER2)-targeted antibody cetuximab and of response to combination therapies against EGFR and HER2 in wild-type KRAS tumor settings may represent a further step toward personalized medicine for patients with colorectal cancer. Herein, we show that transcriptional upregulation of HER2 expression in the absence of HER2 gene amplification is a molecular phenomenon that takes place in EGFR-dependent, wild-type KRAS squamous cell carcinoma (SCC) cells that acquire resistance to cetuximab. Since cetuximab activity against cetuximab-refractory SCC cells can be fully restored in the presence of the anti-HER2 monoclonal antibody trastuzumab, our findings suggest that, beyond HER2 gene amplification, we might need to redefine the threshold values for HER2 positivity to improve the accuracy of the selection of cetuximab-refractory patients with wild-type KRAS that may benefit from receiving a cetuximab/ trastuzumab combination.

HER-2 Expression in Brain Metastases from Colorectal Cancer and Corresponding Primary Tumors: A Case Cohort Series

“…In preclinical models, lapatinib showed greater growth inhibition of TGFβ-activated colon cancer cells than antagonists targeting only ErbB1 or ErbB2 receptors [58]. Moreover, HER-2 amplification seems related to cetuximab resistance [36,59], suggesting that testing HER-2 inhibitors in HER-2 positive CRC population has a strong biological rationale. Actually, the combination of trastuzumab with either lapatinib or pertuzumab is being tested in a pioneer phase II study enrolling KRAS wild-type CRC patients harboring amplification of the HER-2 oncogene that have run out of options [60].…”

Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: Results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients

“…The hypothesis that underlies this study is that cetuximab resistance may occur through the activation of alternate ErbB receptors. Recent efforts have highlighted the role of HER2 signaling as a targetable cetuximab resistance pathway[10,25]. Lapatinib, a small molecule inhibitor of EGFR and HER2, was evaluated as monotherapy in chemo-refractory colorectal cancer[26,27].…”

“…The use of trastuzumab to inhibit HER2 in colorectal cancer was explored in a Phase II study in which enrollment was limited to patients with HER2 overexpression. The low rate of HER2 overexpression in colorectal cancer (observed in 8% of tumors in that trial) [10] resulted in poor enrollment although partial responses were observed in 5 of 7 evaluable patients[28]. Similarly, a Cancer and Leukemia Group B (CALGB) phase II trial of trastuzumab in combination with 5-fluoruracil, leucovorin and oxaliplatin in refractory patients showed some efficacy but again was limited by poor enrollment due to the low rate of HER2-overexpressing colorectal tumors[29].…”

“…One proposed hypothesis for both primary and acquired cetuximab resistance invokes activation of parallel signaling pathways mediated by the alternate ErbB family members, HER2, HER3, and HER4[9]. For example, HER2 upregulation and activity has been consistently demonstrated in a subset of cetuximab-resistant cell lines[10–12], providing a potential target for overcoming cetuximab resistance.…”