In recent years, the TAM (TYRO3, AXL, and MER) family of receptor tyrosine kinases (RTKs) has emerged as attractive targets for oncology therapeutics. Under homeostatic conditions, the TAM RTKs are expressed by a number of immune cells where they play key roles in the negative regulation of the immune response. However, their expression on cancer cells has been specifically associated with epithelial-to-mesenchymal transition, an invasive phenotype, and more generally, with a poor prognostic outcome in human cancers. Here, we sought (1) to establish whether expression of the TAM was sufficient to drive cellular transformation, (2) to demonstrate that RXDX-106, a small molecule inhibitor of TAM RTKs, could inhibit tumors harboring activating TAM gene fusions, and furthermore, (3) to decipher how pharmacological inhibition of TAM signaling pathways both on cancer cells and immune cells would be beneficial, given their complex regulation and intimate relationship in the tumor microenvironment. TAM expression on cancer cells has emerged as one of the key mechanisms of resistance to targeted therapies, particularly to EGFR tyrosine kinase inhibitors (TKI). In addition, novel gene rearrangements (fusions) have been identified in the TCGA database for both Mertk (TMEM87B-Mertk) and Axl (Axl-MBIP) that retain the functionality of the tyrosine kinase domain, but have fusion partners that alter the expression profile or dimerization frequency, respectively. Here, we demonstrate both in vitro and in vivo that expression of either wild type receptors or TMEM87B-MER and AXL-MBIP fusion proteins is sufficient to drive oncogenic transformation by both ligand dependent and independent mechanisms. Treatment of these TAM-expressing cellular populations with RXDX-106 completely inhibits TAM phosphorylation and downstream signaling and, consistent with our signaling data, RXDX-106 completely inhibits cellular proliferation and viability at sub-nanomolar concentrations. Furthermore, we demonstrate that, in the co-culture of TAM-expressing cancer cells with immune cells such as macrophages, TAM ligands such as Gas6 are secreted to drive ligand dependent activation of TAM on cancer cells, leading to their survival and proliferation. In summary, our data suggest that TAM RTKs can act as traditional oncodrivers when activated either in a ligand dependent or ligand independent manner. In addition, we demonstrate that TAM fusions are tractable therapeutic targets and that patients with tumors harboring such molecular alterations may derive clinical benefit from RXDX-106. Finally, we show that RXDX-106 not only has the potential to inhibit cellular proliferation and survival on the cancer cell itself, but also affect the TAM-expressing tumor microenvironment to result in a global anti-cancer environment.

Citation Format: Erin D. Lew, Elizabeth A. Tindall, Joanne Oh, Colin Walsh, Maria Barrera, Heather Ely, Amy Diliberto, Yumi Yokoyama, Gary Li, Amanda Albert. RXDX-106, a novel, selective and potent small molecule TAM (TYRO3, AXL, MER) inhibitor, demonstrates efficacy in TAM-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4191. doi:10.1158/1538-7445.AM2017-4191