Abstract A18: Targeting the MNK kinases for the treatment of NF1-mutant cancers

NF1 mutant cancers are driven by excessive Ras signaling; however, there are currently no effective therapies for these or other Ras-dependent tumors. While MEK inhibitors promote regression of NF1-deficient premalignant lesions, they are ineffective in advanced cancers. Our lab and others have shown that the addition of a PI3K/AKT/mTORC1 inhibitor can co-operate with MEK inhibition to elicit tumor regression in pre-clinical Ras-driven tumor models; however, one concern is that these combinations might not be tolerated in the clinic due to toxicity. Therefore our goal has been to identify more refined, cancer-specific signaling nodes within these pathways. Here we find that eIF4E, a key downstream effector of mTORC1, is constitutively phosphorylated by the MAP kinase-interacting kinases (MNK1 and 2) in NF1 mutant malignant peripheral nerve sheath tumors (MPNSTs). Moreover, we find that combined genetic or chemical suppression of MNK kinases can cooperate with MEK inhibition to reduce cell viability to a similar extent as broad mTOR inhibition. Surprisingly, we find that the MNK kinases are important, previously unrecognized direct targets of the receptor tyrosine kinase inhibitor cabozantinib. Furthermore, we find that cabozantinib but not a more selective MET inhibitor kills NF1-deficient tumor cells when combined with MEK inhibition, and does so in part via eIF4E phosphorylation inhibition. Finally, we show that combining cabozantinib and MEK inhibitors triggers dramatic tumor regression in an aggressive genetically engineered mouse model of MPNSTs. Together, these results identify MNK/eIF4E as a targetable signaling axis when combined with MEK inhibition in these Ras-driven tumors and highlight the utility of both drug repurposing and developing more specific MNK inhibitors for these and other malignancies. Citation Format: Rebecca Lock, Rachel Ingraham, Ophelia Maertens, Bruce Konicek, Sau-chi Yan, Jeremy Graff, Karen Cichowski. Targeting the MNK kinases for the treatment of NF1-mutant cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A18.