Abstract 5194: Pim2 is required for maintaining Multiple Myeloma cell proliferation through modulating mTORC1 pathway.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Multiple Myeloma (MM) is the second most common hematological malignancy. Despite the advances of therapeutic regimens over the last decade, nearly all patients eventually relapse, highlighting the need for additional therapeutic agents. Pim kinases, a family of serine/threonine kinase, are reported to be oncogenic and required for the maintenance of hematological malignancies. Here, consistent with previous reports, we show that Pim2 kinase expression is most highly elevated in MM. Importantly, shRNA knockdown of Pim2 leads to a significant inhibition of MM cell growth, suggesting that Pim2 is critical in maintaining MM malignancy. We developed a potent and specific small molecule inhibitor for the Pim kinases. Inhibition of Pim2 by this molecule suppresses MM cell growth. We find that Pim inhibitor treatment results in the suppression of cell proliferation, but not induction of apoptosis, in all MM cell lines tested. Further, we identified mTORC1 signaling, which is critical for cell proliferation, as significantly repressed by Pim2 inhibition. The two major mTORC1 downstream effectors: P70S6K and 4EBP1 are rapidly dephosphorylated upon Pim inhibitor treatment of MM cells. We are currently investigating the potential signaling modules that may mediate Pim2’s regulation on mTORC1 pathway. Taken together, our findings strongly support Pim2 as a promising therapeutic target in MM, given its distinct expression in MM and essential role in maintaining proliferation. Citation Format: Jing Lu, Tatiana Zavorotinskaya, Yumin Dai, Xiaohong Niu, Joseph Castillo, Janet Sim, Jianjun Yu, Kevin Shannon, Pablo Garcia. Pim2 is required for maintaining Multiple Myeloma cell proliferation through modulating mTORC1 pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5194. doi:10.1158/1538-7445.AM2013-5194