Abstract 2837: Dual inhibition of SHP2 and CDK4/6 leads to immunological memory and immune-mediated anti-tumor activity in a mouse syngeneic model of breast cancer
Authors: Shifrin Nataliya Tovbis , Lee Grace J. , Omaque Neil , Nguyen Tram , Belwafa Amira , Lorenzana Edward G. , Nichols Robert J. , Smith Jacqueline A. , Singh Mallika , Quintana Elsa 
Published: September 2020

Abstract
Allosteric inhibition of the phosphatase SHP2, a key signaling node in the RAS pathway, is a novel, investigational therapeutic strategy for patients bearing tumors with specific oncogenic mutations in this pathway. SHP2 also participates in signal transduction downstream of regulatory immunoreceptors and we have previously shown that inhibition of SHP2 drives anti-tumor immunity through modulation of both innate and adaptive mechanisms in preclinical models (Quintana E. et al, A5019, AACR2019). Rational combination strategies offer an opportunity to optimize the therapeutic potential of SHP2 inhibitors. For example, we have demonstrated that SHP2 inhibition has combinatorial anti-tumor effects with a CDK4/6 inhibitor in several RAS-driven human cancer cell-line derived xenograft models (Lee G. et al, A1322, AACR2019); however, these models use immunocompromised mice, making it impossible to assess an effect of the combination on anti-tumor immunity.
To evaluate the impact of dual SHP2 and CDK4/6 inhibition, we tested this combination in immunocompetent EMT6 tumor-bearing mice. EMT6 is a RAS-driven model of triple-negative breast cancer, which is partially sensitive to SHP2 or CDK4/6 inhibition via cell intrinsic mechanisms. While monotherapy treatment with either RMC-4550, an allosteric inhibitor of SHP2, or abemaciclib, a CDK4/6 inhibitor, resulted in modest tumor growth inhibition, combination treatment led to complete tumor regressions in 40% (4 of 10) of the mice. Furthermore, 30% (3 of 10) of the mice remained tumor-free upon cessation of treatment and, when re-challenged with EMT6 cells tumors failed to grow demonstrating that this dual SHP2-CDK4/6 inhibition results in formation of immunological memory. Combination treatment was well tolerated in mice.
Recently, CDK4/6 inhibitors have been shown to augment anti-tumor immunity via a number of mechanisms, including increases in antigen presentation by the tumor and enhancement of T cell activation. Analysis of the immune landscape in the tumor microenvironment nine days after treatment revealed that RMC-4550 increased the frequency of CD8+T cells and depleted F4/80+ macrophages in EMT6 tumors, and the combination with abemaciclib amplified these changes. Our results suggest that dual SHP2 and CDK4/6 targeting is a promising investigational strategy against tumors driven by mutations in the RAS signaling pathway that combines direct inhibition of cancer cell growth with immunomodulation to potentially achieve robust and durable anti-tumor responses.
Citation Format: Nataliya Tovbis Shifrin, Grace J. Lee, Neil Omaque, Tram Nguyen, Amira Belwafa, Edward G. Lorenzana, Robert J. Nichols, Jacqueline A. Smith, Mallika Singh, Elsa Quintana. Dual inhibition of SHP2 and CDK4/6 leads to immunological memory and immune-mediated anti-tumor activity in a mouse syngeneic model of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2837.