Haratani, Koji

Abstract Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement–positive cancers are limited. In this study, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.04% of cancers. Preliminary analysis from a phase II clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion–positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14–altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion–positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors. Significance: MET rearrangement–positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.

Abstract Background HER2-targeted therapies have been shown clinical benefits in patients with HER2 positive breast and gastric cancers. However, resistance against such targeted therapies eventually develops in most cases. Overexpression of heregulin, a ligand for HER3, has been reported as one of the resistant mechanism against HER2-targeted therapies. Upregulation of heregulin activates HER3-PI3K-AKT signaling, leading to the resistance against HER2-targeted therapies. We investigated the effects of heregulin in cell lines and evaluate its clinical impacts in HER2 positive breast and gastric cancers. Materials and methods We utilized transfected or recombinant heregulin to investigate the effect of heregulin on proliferation and apoptosis of SK-BR-3 and NCI-N87 cell lines treated with lapatinib, trastuzumab, trastuzumab-emtansine and paclitaxel. Clinical data and specimens were obtained from patients with HER2 positive breast and gastric cancers, evaluating their heregulin value from both serum and tissues using ELISA and RT-PCR, respectively. Results Heregulin transfection and recombinant heregulin conferred resistance against treatment with lapatinib, trastuzumab, and weak resistance against trastuzumab-emtansine, but no resistance against paclitaxel in HER2 positive cell lines. Clinical data of heregulin among patients treated with HER2-targeted therapies revealed that patients with relatively high heregulin value tended to have worse prognosis. Conclusions Together these data, overexpression of heregulin may at least in part play a role in resistance against HER2-targeted therapies in HER2 positive cancer patients. Further investigation is warranted to elucidate the relevance of treatments targeting heregulin-HER3-PI3K signaling. Citation Format: Yoshikane Nonagase, Kimio Yonesaka, Satomi Watanabe, Koji Haratani, Takayuki Takahama, Naoki Takegawa, Hiroto Ueda, Hisato Kawakami, Hidetoshi Hayashi, Masayuki Takeda, Haruka Sakamoto, Takao Tamura, Kazuhiko Nakagawa, Junji Tsurutani. Heregulin-induced resistance against HER2-targeted therapies in HER2 positive breast and gastric cancer in vitro and in vivo. [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 2939.