Abstract 4760: Efficacy of EGFR/HER2 duel-kinase inhibitors in PDX models harboring known and novel HER2-mutations
Authors: Wick Michael J. , Farley Monica , Vaught Teresa , Meade Justin , Glassman Michaels , Moriarty Alyssa , Tolcher Anthony W. , Rasco Drew , Patnaik Amita , Papadopoulos Kyriakos P. 
Published: July 2016

Background: Neratinib and afatinib are small molecule therapies that irreversibly bind to the kinase domain of the epidermal growth factor receptors 1 (HER1/EGFR) and 2 (HER2/ERBB2). Afatinib is currently approved for non-small-cell lung cancers harboring acquired EGFR mutations; however both agents have recently reported clinical activity in HER2-mutated breast cancer. HER2 mutations have also been reported in melanoma and colorectal cancer and at least two mutations (S310F/V777L) have been shown to affect EGFR/HER2 signaling. Whether other reported or novel mutations are important in EGFR/HER2 signaling in colorectal and other cancer types is unclear. To better understand effects of HER2 mutations we characterized a panel of patient-derived xenograft tumor models representing colorectal, ovary, pancreas and endometrial cancers using RNA- and DNA-based sequencing. EGFR and HER2 expression was also quantitated using immunohistochemistry (IHC). Models identified positive for HER2 mutation by sequencing were evaluated in vivo, testing antitumor activity of neratinib, afatinib and other targeted therapies.

Methods: START-PDX models were established from tissue or fluid samples as previously described. DNA or RNA were extracted and subjected to NGS and HER2 and other cancer-related mutations reported; growth factor receptor densities were interrogated using standard IHC. Drug studies were performed evaluating sensitivity of models to single agent neratinib, afatinib, lapatinib, trastuzumab and T-DM1 administered on standard treatment regimens. Study endpoints included tumor volume and time from treatment initiation with T/C values and tumor regression reported at study completion.

Results: DNA and RNA sequence analysis of 300 models identified eleven HER2 mutations including six previously reported in COSMIC (S310F, A386D, H473R, D582N, V777L, R678Q) and five novel variants (R330Q, G366R, Q398K, I628T, A1216D) in thirteen total models. High EGFR staining was reported in two colorectal models: ST427 (HER2V777L) and ST428 (HER2A1216D) while high EGFR and HER2 staining was reported in a lung model designated ST1243 (HER2S310F). In vivo treatment with neratinib or afatinib resulted in tumor growth inhibition in some tested models including ST022 (HER2G366R/R678Q) ovary and ST204 (HER2A386D) pancreas and tumor regressions were reported with either agent in the ST427 (HER2V777L) colorectal line. Neratinib or afatinib were also found active in one each of four tested endometrial models. Lapatinib, trastuzumab and T-DM1 were inactive in all tested HER2-mutant models.

Conclusion: We have sequenced a panel of PDX models and identified six previously reported and five novel HER-2 mutations in thirteen models which we screened in vivo for sensitivity to EGFR/HER2 duel kinase inhibitors and HER2-targeting therapies with the colorectal model ST427 (HER2V777L) identified as most sensitive to neratinib and afatinib.

Citation Format: Michael J. Wick, Monica Farley, Teresa Vaught, Justin Meade, Michaels Glassman, Alyssa Moriarty, Anthony W. Tolcher, Drew Rasco, Amita Patnaik, Kyriakos P. Papadopoulos. Efficacy of EGFR/HER2 duel-kinase inhibitors in PDX models harboring known and novel HER2-mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4760.