Abstract P6-17-15: Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models
Authors: SM Kavuri, V Devarakonda, LC Williams, S Seker, JT Lei, P Singh, A Han, M Anurag, KR Holloway, AL Welm, MJ Ellis
Journal: Cancer Research (2019)

Abstract Background Until recently, HER2 gene amplification was the only mechanism of HER2 activation recognized. However, activating HER2 mutations have been noted in different cancer types. A trials of HER2 mutant breast cancer and the subsequent SUMMIT trial data have shown that monotherapy with the pan-HER drug neratinib as showed clinical efficacy, but with poor response durability. This study therefore investigates the preclinical efficacy of anti HER2 agents alone or in combination with endocrine therapy agents or in combination with CDK4/6 inhibitors using ER+/HER2 mutant cell lines and ex vivo HER2 mutant patient derived xenograft (PDX) model to define a more effective treatment approach. Methods ER+ breast cancer cell lines (T47D and MCF7) stably expressing HER2V777L, and ER+/HER2 mutant PDX model (HER2G778_P780 dup) were used to examine HER2 signaling and drug responses. Signaling downstream mutant HER2 was examined by immunoblot analysis. Effects of neratinib alone, neratinib + fulvestrant, and neratinib + abemaciclib on cell growth were examined in ER+/HER2 mutant cell lines and in an ex vivo HER2G778_P780 dup. Results We found that MCF7/T47D cells expressing HER2V777L and HER2G778_P780 dup PDX tumors showed strongly activated autophosphorylation of HER2 and increased expression of CDK4, CDK6, phospho-Rb, and cyclin D1 as compared to MCF7/T47D cells expressing HER2WT or ER+/non-HER2mut PDX modes, suggesting that HER2 mutations preferentially depend on CDK4/6 signaling for cell growth. Additionally, we showed that activating MCF7 HER2 V777L cause resistance to endocrine therapy treatment (fulvestrant IC50 &amp;gt;5μM). Further, we show that neratinib alone is effective at higher concentrations (IC50 &amp;lt; 2μM) in MCF7/HER2 V777L cells. We also demonstrate that abemaciclib alone exhibited moderate activity against MCF7 HER2 V777L cells (IC50 &amp;lt; 0.4μM) and additional activity in combination with neratinib (IC50 &amp;lt; 0.06μM) was seen. Moreover, ex vivo HER2 G778_P780 dup cells are relatively resistant to fulvestrant alone (IC50 &amp;lt; 0.2μM), neratinib alone (IC50 &amp;lt; 0.006μM), abemaciclib alone (IC50 &amp;lt; 0.04μM), and neratinib in combination with abemaciclib (IC50 &amp;lt; 0.005μM), suggesting that patients harboring ER+/HER2-mutant tumors may benefit from neratinib in combination with abemaciclib. Conclusion These preclinical data suggest that neratinib monotherapy may not be effective to treat ER+/HER2 mutant patients and we propose that simultaneous targeting of both HER2 and the CDK4/6 axis will be required for effective treatment of ER+ breast cancers harboring HER2 activating mutations. Citation Format: Kavuri SM, Devarakonda V, Williams LC, Seker S, Lei JT, Singh P, Han A, Anurag M, Holloway KR, Welm AL, Ellis MJ. Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-15.