Abstract 3195: DYRK1B inhibitors prevent pharmacologic quiescence and sensitize lung cancers to EGFR inhibitors

Abstract

Abstract Many oncoproteins that activate signaling dysregulate cell growth by activating the cyclinD/cdk4, cdk6 complex and abrogate in the G1 checkpoint (mutant RAS, BRAF, PIK3CA, EGFR etc.) Inhibition of these oncoproteins inhibits cyclinD expression and kinase activity as well as RB phosphorylation and results in G0/G1 arrest and apoptosis. It has been posted that cells arrested in G0/G1 are protected from cell death. DYRK1B kinase plays an important role in physiologic quiescence by maintaining the viability of cells arrested in the G0/G1 phases of the cell cycle. DYRK1B regulates the G0/G1 transition by phosphorylating cyclin D1 and p27, whereby destabilizing cyclin D1 and stabilizing p27. The balance between these two proteins is essential for maintenance of cells in G0 (quiescent) state. DYRK1B is sparsely expressed in healthy tissues yet is overexpressed in patient samples with variety of neoplasms, including NSCLC. Cancer and normal cells exhibit differential sensitivity to DYRK1B inhibition. Whereas DYRK1B appears essential for survival of cancer cells either endogenously expressed or upregulated, its inhibition in healthy cells was not cytotoxic and had no effect on the cell cycle distribution. We hypothesized that if DYRK1B is required for maintenance of quiescence, its inhibition would enhance the effects of inhibitors of oncogenic signaling. We used a selective, ATP competitive DYRK1B inhibitor to test this idea. EGFR inhibitors are effective in non-small cell lung cancers with mutant EGFR and induce G0/G1 block and some apoptosis. These drugs significantly extend survival, but acquired resistance almost always supervenes. In vitro, the anti-proliferative response of lung tumors with mutant EGFR to EGFR inhibitors was shown to be primarily due to the entry of cells into a quiescent (G0) state associated with an induction of DYRK1B expression. Moreover, addition of a DYRK1B inhibitor reversed the quiescent state in cells exposed to EGFR inhibitors. Combined therapy of EGFR TKIs and the DYRK1B inhibitor significantly enhanced the antitumor response compare to either drug alone. Specifically, it is shown that treatment with osimertinib results in an increase of cells in G0 state: 63% as compared to non-treated cells, 29%. The induction of quiescence is prevented when cells are treated with the combination of osimertinib and DYRK1B inhibitor and massive apoptosis is observed: 62% compared to 12% with osimertinib alone. It is important to note that co-treatment with DYRK1B inhibitor not only prevented the entry of cancer cells into quiescence but also depleted pre-existent reservoir of quiescent cancer cells. The results suggest that inhibition of EGFR causes tumor cells to enter into a DYRK1B-dependent quiescent state in which DYRK1B is required for their survival. Inhibition of DYRK1B dramatically enhances the antitumor activity of EGFR inhibition and may improve outcome in patients. Citation Format: Maria Vilenchik, Alexandra Kuznetsova, Michael Frid, Yuriy Gankin, Marc Duey, Neal Rosen. DYRK1B inhibitors prevent pharmacologic quiescence and sensitize lung cancers to EGFR inhibitors [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 3195. doi:10.1158/1538-7445.AM2017-3195