Abstract 2979: The effect of interferon gamma on melanoma progression under MAPK inhibitor therapy

Abstract

Abstract About half of metastatic cutaneous melanoma harbor a mutation in the BRAF protein, causing constitutive activation of the MAPK pathway. Currently, patients with such mutation are treated with MAPK pathway inhibitors (MAPKi) targeting the mutant BRAF and its downstream MEK proteins. However, within a span of 6-12 months, these patients will relapse, and their tumors will acquire resistance to this treatment. In this project, we aim to understand the role of IFN gamma (IFNg) to help us determine if the resistance phenotype differs between cells exposed with MAPKi alone versus cells treated with MAPKi and IFNg. Previous literature has reported on the development of a dedifferentiated resistance phenotype which was characterized by a downregulation of MITF and an upregulation of AXL proteins. However, the patient-derived transcriptomic data comparing paired tumors pre- and post-MAPKi therapy did not show such changes in MITF or AXL levels. We posit that the discrepancy may be because most of the earlier studies on MAPKi resistance were done in vitro or immune-suppressed in vivo models. Melanoma biopsies from patients responding to MAPKi treatment showed a substantial increase in the tumor-infiltrating T cell and other immune cells. One of the most dominant immune factors produced by the T cells is the interferon gamma (IFNg). Intriguingly, our data show that IFNg, in the presence of MAPKi, can suppress the dedifferentiation switch that is induced by MAPKi-alone. Specifically, through serial western blots, we discovered that MAPKi and IFNg reduced the previously reported AXL upregulation and MITF downregulation in four different mutant BRAF melanoma lines. RNA sequencing from the same time points revealed that melanoma treated with MAPKi and IFNg upregulate IFN-stimulated genes that are typically expressed by immune cells; this leads us to believe that some novel transcriptomic programs have been activated by the combination of MAPKi and IFNg. By solely examining one immune factor, IFNg, we discovered one potential explanation for the discrepancy in the prevalence of MAPKi-induced dedifferentiation phenotype in the patient-derived melanoma samples. We are in the midst of performing drug screening experiments on MAPKi and IFNg-resistant melanoma lines in order to discover novel therapeutic vulnerabilities that were not observed with MAPKi-alone. Finally, by taking into account the secreted factors in the tumor microenvironment, our study can provide a more accurate depiction of MAPKi resistance evolution in mutant BRAF melanoma patients. Citation Format: Kevin Chen, Rachel McMillan, Mona Chatrizeh, Willy Hugo. The effect of interferon gamma on melanoma progression under MAPK inhibitor therapy [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 2979.