Acral and mucosal melanomas (AMM's) arise from sun-protected sites, disproportionately impact darker-skinned individuals and exact a higher mortality than common types of cutaneous melanoma. Genetically, AMM's harbor more alterations of KIT compared to typical CM's. As KIT-mutated melanomas remain largely treatment resistant, we set out to create a faithful murine KIT-driven allograft model to define newer therapeutic strategies. Using the prevalent human KIT activating mutation, the murine mKIT cellular avatars show features of transformation in vitro and tumorigenic in immunocompetent C57BL/6J mice. Compared to its vector-controlled cells (mVec), mKIT cells proliferate more rapidly, exhibit greater chromosoma... More
Acral and mucosal melanomas (AMM's) arise from sun-protected sites, disproportionately impact darker-skinned individuals and exact a higher mortality than common types of cutaneous melanoma. Genetically, AMM's harbor more alterations of KIT compared to typical CM's. As KIT-mutated melanomas remain largely treatment resistant, we set out to create a faithful murine KIT-driven allograft model to define newer therapeutic strategies. Using the prevalent human KIT activating mutation, the murine mKIT cellular avatars show features of transformation in vitro and tumorigenic in immunocompetent C57BL/6J mice. Compared to its vector-controlled cells (mVec), mKIT cells proliferate more rapidly, exhibit greater chromosomal aberrations, and sustain 3D spheroid expansion and aggressive tumor growth in C57BL/6J mice. We further verified the functional dependence of these cells on KIT with both genetic and pharmacologic suppression. Using these cells, we performed a screen of 199 kinase inhibitors and identified a selective vulnerability to Chk1/ATR inhibition in the KIT-activated cells. Mechanistically, we subsequently showed that KIT induces a significantly increased level of replication stress compared to mVec cells. These results showcase an allograft model of human KIT-driven melanomas, which uncovered an unappreciated role for replication stress in KIT melanomagenesis and implicated a possible therapeutic strategy with Chk1/ATR inhibitors.
