Abstract 1013: Understanding the molecular pathways underlying radio-sensitization of non-small cell lung cancer (NSCLC) by vitamin D (EB1089)

Ionization radiation (IR) is an integral component of lung cancer treatment. However, disease recurrence represents a significant barrier to effective therapy. One explanation for the difficulties associated with treatment of NSCLC could be the promotion of autophagy, a cytoprotective signaling pathway that controls the degradation and recycling of cellular components. Cytoprotective autophagy may be one of the primary causes for the development of resistance to standard therapies. In recently published studies (Sharma et al, Autophagy), we showed that the vitamin D analog, EB 1089, leads to conversion of the cytoprotective autophagy induced by radiation alone to a novel ‘cytostatic’ form of autophagy. While pharmacological and genetic inhibition of autophagy increased sensitivity to radiation, interference with autophagy reversed the radio-sensitization by EB 1089 (or Vitamin D3) in H460 and A549 NSCLC cells. These studies demonstrated a switch between the cytoprotective and cytostatic roles of autophagy in response to radiation alone and the combination of EB 1089 (or Vitamin D3) and radiation. AMPK, an energy sensor, has been shown to be involved in regulating autophagy via the AMPK-mTOR pathway. We observed an increase in phosphorylated AMPK (and ULK-1, which is downstream of AMPK) with the combination treatment of IR and EB 1089. Both pharmacological and genetic inhibition of AMPK, reverted the radio-sensitization effects of EB 1089, implicating AMPK in radio-sensitization. Studies conducted with NSCLC cell lines both wt and mutant or null in p53 indicated that functional p53 was required to radio-sensitize tumor cells with the combination treatment. p53 appears to promote AMPK upregulation via sestrin. Finally, studies to determine the potential involvement of NF-kB in radiation sensitization showed degradation of IKB-α in response to IR alone that was suppressed by EB 1089, indicating NF-kB9s involvement in the initiation of cytoprotective autophagy by radiation Overall, these studies suggest that the use of vitamin D or a vitamin D analogue could increase sensitization to radiation treatment for lung cancer. Citation Format: Khushboo Sharma, Theresa Thekkudan, David Gewirtz, Hisashi Harada, Frank Torti, Suzy Torti. Understanding the molecular pathways underlying radio-sensitization of non-small cell lung cancer (NSCLC) by vitamin D (EB1089). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1013. doi:10.1158/1538-7445.AM2015-1013