Abstract A30: Radiation resistance of human lung cancer stem cells (CSCs)

Abstract

Abstract Non-small cell lung cancer (NSCLC), the most common form of lung cancer, is treated with tumor resection and chemotherapy, with ionizing radiation (IR) treatment and chemotherapy used for patients with unresectable tumors. Despite improvements in medical management, 5-year survival rates for NSCLC remain low. Evidence suggests that resistance to radio- and chemotherapy is associated with cancer stem cells (CSCs), which are undifferentiated cells with the capacity to self-renew and differentiate, restoring the tumor cell population following treatment. However, the mechanisms through which lung CSCs evade and resist radiation therapy remain poorly studied. We previously reported on our ability to isolate, culture, and assay human lung CSCs from cultured cell lines. We found the stem cell factor (SCF) and its receptor c-kit functions in a crucial pathway for the self-renewal and proliferation of human lung CSCs. We discovered that a combination of cisplatin (to eradicate bulk tumor cells) and agents targeting SCF/c-kit signaling in CSCs (e.g., antibody neutralizing SCF and anti-c-kit RTK inhibitors) is an effective therapy against NSCLC in vitro. Here we extend our work to CSCs derived from primary NSCLC surgical tumor specimens. We analyzed lung CSC resistance to ionizing radiation (IR) and molecular mechanisms associated with CSC radioresistance. We found that human lung CSC radioresistance is mediated by preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. Tyrosine kinase inhibitors with anti c-kit activity (e.g., imatinib, dovitinib, sunitinib, and axitinib) were compared for their ability to abrogate lung CSC proliferation and potentiate effect of IR on NSCLC. We found that lung CSCs proliferation was abrogated by all of the four c-kit inhibitors; however, axitinib showed the most profound anti-CSC effect. The combination of IR treatment with SCF/ckit pathway inhibition eliminated bulk NSCLC cells and radiation resistant CSCs.