Abstract 4756: A SPP1-EGFR pathway links stem-like properties of KRAS-mutated lung cancer to radiation resistance
Authors: Wang Meng , Han Jing , Marcar Lynnette , Black Josh , Liu Qi , Li Xiangyong , Nagulapalli Kshithija , Sequist Lecia V. , Mak Raymond H. , Benes Cyril H. , Hong Theodore S. , Gurtner Kristin , Krause Mechthild , Baumann Michael , Kang Jing X. , Whetstine Johnathan R. , Willers Henning 
Published: July 2017

Lung cancers with activating mutations in the KRAS oncogene present a major clinical challenge due to poor prognosis and frequent treatment resistance, particularly to agents targeting the epidermal growth factor receptor (EGFR). For many years, it has been known that mutations in KRAS enhance cellular resistance to ionizing radiation (IR). Clinical data are emerging suggesting that the radioresistance of KRASmut cancer cells that is observed in the laboratory is also seen in patients. However, the underlying mechanisms of mutant KRAS-associated radioresistance is understudied and poorly understood. Cancer stem cells (CSC), also referred to as tumor-initiating cells, may promote metastases development and recurrence after therapy. Generally, cancer cells with CSC-like phenotypes or markers have been found to be radioresistant. Enhanced DNA damage response and repair pathways have been discussed as one underlying mechanism. Interestingly, mutant KRAS has been recently linked to CSC-like phenotypes such as tumor initiation, anchorage independence, and self-renewal. Here, we characterized a radioresistant phenotype associated with KRAS mutated lung cancer cells, xenografts, and patients. CSC-like cells were defined as tumor-initiating cells. Genomic, biochemical, and cell-based assays were used to identify candidates for targeting KRAS mutation-mediated radiation resistance. Radiation resistance is conferred by a CSC-like subpopulation that is characterized by condensed chromatin, high CD133 expression, invasive potential, and tumor-initiating properties. Osteopontin, the gene product of SPP1, promotes aspects of this phenotype including radiation resistance and acts in the same pathway as the EGFR. SPP1/EGFR-dependent chromatin condensation not only protects cells against radiation-induced DNA damage but also downregulates putative negative regulators of CSC-like properties, including CRMP1 and BIM. This phenotype defines a subset of KRAS mutated lung cancers that is enriched for co-occurring TP53 mutations. In conclusions, markers and mechanisms of resistance to radiation therapy in lung and other cancers are poorly characterized. Our data provide novel insight into the aggressive biology of KRAS mutant cancers and have major implications for strategies to overcome the radiation resistance associated with this genotype.

Citation Format: Meng Wang, Jing Han, Lynnette Marcar, Josh Black, Qi Liu, Xiangyong Li, Kshithija Nagulapalli, Lecia V. Sequist, Raymond H. Mak, Cyril H. Benes, Theodore S. Hong, Kristin Gurtner, Mechthild Krause, Michael Baumann, Jing X. Kang, Johnathan R. Whetstine, Henning Willers. A SPP1-EGFR pathway links stem-like properties of KRAS-mutated lung cancer to radiation resistance [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 4756. doi:10.1158/1538-7445.AM2017-4756