LAUSR

One of the major factors contributing to poor outcomes for patients with ovarian cancer is the persistence of dormant, drug resistant cancer cells after primary surgery and chemotherapy. Recurrent, progressively growing ovarian cancer metastases are generally well vascularized and may only have a small fraction of cancer cells undergoing autophagy. By contrast, the persistent, drug resistant, dormant cancer cells that remain on the peritoneal cavity after conventional treatment tend to be poorly vascularized. In this nutrient-poor, avascular microenvironment autophagy is widespread and can be found in more than 80% of cases. Drugs that regulate survival in autophagic cancer cells may be much more active when administered as maintenance therapy than when used to treat gross primary or recurrent disease. Using unbiased siRNA screens, we have identified target genes that regulate the survival of ovarian cancer cells that are undergoing autophagy that has been induced by the re-expression of DIRAS3 or by amino acid starvation. Knockdown of the anaplastic lymphoma kinase (ALK) significantly reduced survival of ovarian cancer cells that were undergoing autophagy. Importantly, the FDA-approved ALK inhibitor, Crizotinib, exhibited significantly greater toxicity after induction of autophagy by upregulation of DIRAS3 (ARHI) in OVCAR8, CAOV3, and SKOv3 ovarian cancer cells. Induction of autophagy by upregulation of DIRAS3 in SKOv3 ovarian cancer cells reduced the IC50 of Crizotinib from 7.44µM ± 0.04708 to 2.129µM ± 0.06152 (P Citation Format: Alicia M. Blessing, Yan Wang, Weiqun Mao, Lan Pang, Zhen Lu, Robert C. Bast. Autophagic ovarian cancer cells exhibit substantially enhanced sensitivity to Crizotinib [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 3313. doi:10.1158/1538-7445.AM2017-3313