Abstract 132: HER2 activating mutations are potential targets for colorectal cancer treatment
Authors: Kavuri Shyam M. , Jain Naveen , Galimi Francesco , Cottino Francesca , Searleman Adam C. , Shen Wei , Trusolino Livio , Jacobs Samuel A. , Bertotti Andrea , Bose Ron 
Published: August 2015

Abstract
Background:
Cancer genome sequencing is identifying new genetic alterations and new driver events in human cancers. The Cancer Genome Atlas (TCGA) colorectal cancer project found that 7% of colorectal cancer (CRC) patients have HER2 somatic mutations or HER2 gene amplification. HER2 gene amplification in CRC is known to produce resistance to the EGFR monoclonal antibodies, cetuximab and panitumumab. However, the impact of HER2 somatic mutations in CRC has not been studied and it is open question as to whether HER2 mutations are clinically important in CRC.
Results:
Introduction of the HER2 mutations, S310F, L755S, V777L, and V842I, into immortalized colon epithelial cells increased cell signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of HER2 V842I mutation into colorectal cancer cell lines produced resistance to the EGFR antibodies, cetuximab and panitumumab. HER2 mutations are potently inhibited by low nanomolar doses of the second generation, irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab resistant, quadruple WT (KRAS, NRAS, BRAF, and PIK3CA WT) colorectal cancer patient derived xenografts (PDX’s) identified 4 PDX's with HER2 mutations (4/48 = 8.3%). Treatment of these PDX's with a single HER2 targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2 targeted therapy with trastuzumab plus a tyrosine kinase inhibitor produced durable shrinkage of the tumors in mice. After the final timepoint in each PDX experiment, the mice were sacrificed and the tumors excised. The tumor histology demonstrated that dual HER2 targeted therapy caused reduction in tumor cellularity and acquisition of more differentiated features.
Conclusions:
These data demonstrate that HER2 activating mutations are a new drug resistance mechanism to EGFR monoclonal antibodies. More importantly, these data suggest that HER2 activating mutations may themselves be a drug target for the treatment of colorectal cancer. These data form a strong pre-clinical rationale for clinical trials targeting HER2 activating mutations in metastatic CRC patients. The NSABP Foundation is in the design stage for such a clinical trial and will use its living patient biorepository (MPR-1 trial) that contains 1350 colorectal cancer patients to identify subjects for this trial.
Citation Format: Shyam M. Kavuri, Naveen Jain, Francesco Galimi, Francesca Cottino, Adam C. Searleman, Wei Shen, Livio Trusolino, Samuel A. Jacobs, Andrea Bertotti, Ron Bose. HER2 activating mutations are potential targets for colorectal cancer treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 132. doi:10.1158/1538-7445.AM2015-132