Abstract 4291: Oncogenic ALK regulates cell cycle progression via CDK1: Implications for therapy

Abstract Pharmacologic inhibition of oncogenic ALK can yield clinical responses in a variety of cancer types, including non-small cell lung cancer, anaplastic large-cell lymphoma, and neuroblastoma; however, de novo and acquired resistance remain major problems. As is seen with inhibition of other oncogenic receptor tyrosine kinases, ALK inhibition primarily induces G1 cell cycle arrest. However, we and others have also observed a role for receptor tyrosine kinases in regulating G2/M progression. For instance, oncogenic HER2 has been shown to directly phosphorylate tyrosine 15 of CDK1, the mitosis promoting factor. This tyrosine is also the well-known substrate of WEE1 and serves to inactivate CDK1 kinase activity as a critical component of the G2-M checkpoint. In the current study, we aimed to determine if oncogenic ALK functions in a similar capacity. We used recombinant proteins to demonstrate that ALK is also capable of directly phosphorylating tyrosine 15 of CDK1. Further, combined inhibition of ALK and WEE1 with crizotinib and AZD-1775 leads to greater reduction in pY15-CDK1 than either agent alone in ALK-amplified neuroblastoma cells. These findings suggest a model where oncogenic ALK and WEE1 provide redundant regulation of the G2-M checkpoint, which may be critical in cancer cells that have lost some of the usual complement of checkpoint controls, such as p53. Consequently, either ALK or WEE1 activity would be sufficient to maintain appropriate cell cycle regulation, while dual blockade would allow mitosis to proceed unchecked. In agreement with these predictions, we performed live cell imaging and observed that combined inhibition of ALK and WEE1 leads to aberrant mitotic progression and mitotic catastrophe. Further, this combination yields greater anti-proliferative activity than either agent alone in ALK-driven models. Thus, this therapeutic strategy holds great promise for ALK-driven cancers. Citation Format: Kathleen A. Scorsone, Sonal Gahlawat, Siddhartha Tyagi, Mayra C. Orellana, Thomas F. Westbrook, Ronald J. Bernardi. Oncogenic ALK regulates cell cycle progression via CDK1: Implications for therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4291.