Immuno-Oncological Efficacy of RXDX-106, a Novel Small Molecule Inhibitor of the TAM (TYRO3, AXL, MER) Family of Kinases

Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant anti-tumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild type mice and was abrogated in immunodeficient mice, suggesting that the anti-tumor activity of RXDX-106 is in part due to the presence of immune cells. RXDX-106-mediated TGI was associated with increased tumor-infiltrating leukocytes (TILs), M1-polarized intra-tumoral macrophages, and activation of NK cells. RXDX-106 proportionally increased intra-tumoral CD8+ T cells and T cell function as indicated by both IFN-γ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intra-tumoral macrophages and dendritic cells (DCs), leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced anti-tumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types.

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