Abstract A22: Effects of CDK4/6/MAPK targeting combinations on melanoma and the tumor immune microenvironment

Abstract

Abstract Trials utilizing cyclin-dependent kinases 4/6 (CDK4/6) inhibitor alone or in combination with BRAF and MEK inhibitors are under way in melanoma, but their use needs to be optimized. MEK plus CDK4/6i combinations lead to tumor regressions in vivo; however, residual disease and acquired resistance frequently persisted. Previously, we showed that amplification or mutation of NRAS was associated with acquired resistance in in vivo mutant NRAS models and mutant BRAF patient samples, respectively. These mechanisms led to upregulation of mTOR-S6 pathway. Here, we observed upregulation of dormancy signature and increased NR2F1 expression in residual disease. To further identify targetable pathway alterations associated with these resistance mechanisms, we have established longitudinal cell lines from multiple metastases from a single patient on the LOGIC2 (BRAF-MEK-CDK4/6i) trial. RPPA analysis highlights differences between the lines that we are further analyzing in functional assays. There is also increasing evidence that CDK4/6 inhibitors (CDK4/6i) may regulate the tumor immune microenvironment. We show that MEK plus CD4/6i led to better control of tumor growth in syngeneic models compared to immune-deficient NSG mice. The response to MEK plus CDK4/6i was associated with increased infiltration of CD8 positive T cells and T-cell activation markers. Together, we aim to identify mechanisms underlying resistance/tolerance to MEK plus CDK4/6i and to determine effects on the tumor immune microenvironment to inform potential new treatment strategies. Citation Format: Jessica L.F. Teh, Phil F. Cheng, Dan E. Erkes, Timothy J. Purwin, Conroy Field, Connor Hollingworth, Julio Aguirre-Ghiso, Mitch P. Levesque, Reinhard Dummer, Andrew E. Aplin. Effects of CDK4/6/MAPK targeting combinations on melanoma and the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A22.