Abstract P117: Oncogenic Kit induces replication stress and induces Chk1/ATR inhibitor sensitivity in melanoma

Abstract

Abstract Contrary to cutaneous melanoma (CM), Acral and mucosal melanomas (AMM’s) lack effective therapy and exact a higher mortality. Since amplifications and point mutations of KIT are common in AMM, we created a multi-stage murine cellular model of human KIT melanomas (i.e. mKitK641E lines) based on the most common KIT mutation in human melanoma (p.K642E). Compared to its vector-controlled cells (mVec), mKitK641E cells exhibit greater chromosomal aberrations, and sustain 3D spheroid forming capability and aggressive tumor growth in C57BL/6J mice. In addition, DNA replication/RNA processing and ribosomal biogenesis pathways associated with KitK641E transformation. Surprisingly, an unbiased comparative drug screen uncovered a selective vulnerability to Chk1 inhibition in the KitK641E activated cells. mKitK641E cells displayed >6-fold greater sensitivity compared to mVec cells (GI50=1.5 µM vs 10 µM) for Chk1 inhibitor PF477736 treatment. Furthermore, we proved that KitK641E induces profound DNA replication stress as evidenced by increased levels of γ-H2AX and p-RPA32Ser33 in replicating cells and defective replication fork progression. Thus, mKitK641E represents a novel model to study the biology of KIT-driven melanoma and therapy development. Citation Format: Ching-Ni Njauw, Zhenyu Ji, Hensin Tsao, Antoine Simoneau, Raj Kumar, Keith T. Flaherty, Lee Zou, Duc Minh Pham. Oncogenic Kit induces replication stress and induces Chk1/ATR inhibitor sensitivity in melanoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P117.