Abstract IA22: Integrating immunotherapy and targeted therapy in breast cancer

Abstract

Therapeutic resistance is a major obstacle in the clinic for cancer treatment. Utilizing our novel genetically engineered mouse models (GEMMs) of cancer driven by inducible expression of oncogenic PIK3CA or HER2, coupled with pharmacologic approaches, we identified several significant resistance mechanisms to PI3K- or HER2-targeted therapy. For example, we found spontaneous focal amplification of Met and Myc, recurrent mutations in Ras and β-catenin, and compensatory activation of the MAPK pathway render resistance to PI3K inhibition. We recently identified Cyclin D1-CDK4 mediated resistance to HER2-targeted therapy through a signaling feedback loop. Beyond suppressing cell cycle progression, we found that CDK4/6 inhibitors promote antitumor immunity and increase cytotoxic T cell-mediated clearance of tumor cells, which is further enhanced by the addition of immune checkpoint blockade. More importantly, these results led to the design of clinical trials with CDK4/6 inhibitor in combination with HER2-targeted therapy and PD1 blockade for patients with metastatic, refractory HER2+ breast cancer. Parallel to GEMMs, we have led the efforts to establish and characterize novel cancer patient-derived xenograft (PDX) models, with an emphasis on brain metastases, an emerging clinical challenge. I will discuss how we have used these models to discover therapeutic strategies that integrate targeted therapy and immunotherapy to overcome resistance and to drive these discoveries to the clinical trials. Citation Format: Jean Zhao. Integrating immunotherapy and targeted therapy in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA22.