Abstract 846: Inhibition of lysophosphatidic acid receptor 1 radiosensitizes lung cancer cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Despite advances in diagnostic and therapeutic modalities, lung cancer remains the leading cause of cancer-related mortality in the United States. In most cases, lung cancer presents as an unresectable mass requiring a combination of chemotherapy and radiotherapy (CRT) for treatment. A barrier to efficacy of this treatment is radioresistance. Radiation induced activation of pro-survival pathways are currently thought to play an important role in radioresistance. The enzyme cytosolic phospholipase A2 (cPLA2) has been identified as a key component in radiation induced pro-suvival pathways. Ionizing radiation activates cPLA2, which then cleaves phosphatidylcholine (PC) to yield lysophosphatidylcholine (LPC). LPC is then converted to lysophosphatidic acid (LPA) by autotaxin (ATX). LPA binds to distinct G-protein coupled receptors (GPCRs) on the plasma membrane; LPA1, LPA2 and LPA3, which are encoded by the endothelial differentiation gene family. These receptors are involved in the regulation of various aspects of cancer, including proliferation, migration and metastasis. Previously, we have shown that inhibition of cPLA2, as well as inhibition of ATX, was sufficient to enhance the sensitivity of cancer cells to radiation. However, the question remains as to whether inhibition of LPA receptor activity would have a similar effect. Thus, we studied the role of LPA receptors as mediators of radioresponse in human A549 and murine Lewis Lung Carcinoma (LLC) cell models. Quantitative polymerase chain reaction (QPCR) analysis of lung cancer cells showed that LPA1 was highly expressed in LLC and A549, and that both cell lines had nearly undetectable levels of LPA2 and LPA3 mRNA. Hence, we used Ki16425 and VPC12249, specific inhibitors of LPA1 and LPA3, to study the effect of LPA1 inhibition on clonogenic survival, cellular proliferation and invasion after irradiation. We found that pre-treatment of LLC and A549 cells with 10µM Ki16425 or 10µM VPC12249 significantly attenuated cell proliferation and viability after irradiation. Pre-treatment of LLC cells with 10µM Ki16425 or 10µM VPC12249 also reduced clonogenic survival. Transwell cell-invasion assays showed that the combination of LPA1 inhibitors with irradiation significantly reduced LPA-induced cell invasion in A549 and LLC cells. To investigate a potential mechanism for these effects, we also determined the activation of AKT and ERK signaling pathways. Inhibition of LPA1 resulted in reduced radiation-induced phosphorylation of both AKT and ERK. Overall, our results indicate that LPA1 is a mediator of pro-survival signaling in the adaptive response to radiation, and could serve as a viable target for enhancing the efficacy of radiation therapy of lung cancer. Note: This abstract was not presented at the meeting. Citation Format: David Y.A. Dadey, Rowan M. Karvas, Rama Kotipatruni, Jerry Jaboin, Dennis Hallahan, Dinesh Thotala. Inhibition of lysophosphatidic acid receptor 1 radiosensitizes lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 846. doi:10.1158/1538-7445.AM2014-846