Radioresistance in lung cancera molecular approach

Abstract

Lung cancer is responsible for more than 20% of deaths produced because of cancer worldwide, and non-small cell lung cancer is the cause of 85% of fatalities in patients diagnosed with lung cancer. The first line of treatment for lung cancer is still surgical resection, when possible, and chemotherapy, and for unresectable tumors, radiation is the primary tool to control the disease. Unfortunately, non-small cell lung cancer is often diagnosed in advanced stages, and recurrences after a successful tumor control are frequent. For tumors that have been previously treated, the possibilities of getting them under control are, most of the time, slim. This difficulty in treatment is because tumors acquire resistance to the treatments they had been exposed. The research exposed here investigates the profile of non-small lung cancer cells that have survived radiation, trying to elucidate the characteristics that make them radioresistant and allow for the re-establishment of the tumor, and whether they can be eliminated. Our results show that non-small cell lung cancer cells that have survived radiation exhibit cancer stem cell traits, like the increased ability to grow in attachment independent conditions, and overexpress stem markers (such as CD44 and CD166) and stem related transcription factors, like OCT4, SOX2, or b-catenin. Moreover, the same populations expressed epithelial to mesenchymal transition markers, such as SNAIL, TWIST, Vimentin, or N-cadherin. With the data exposed in this document, we showed that cells that survived radiation can be eliminated by inhibiting HSP90, a chaperone involved in the correct folding and stabilization of many essential signaling pathway proteins. The inhibition of HSP90, combined with radiation, impaired tumor cell growth by dysregulating DNA damage repair pathways, leading the cells to cell cycle arrest and senescence at the same time that switches off important prosurvival signaling such as PI3K/AKT. By comparing radioresistant cell lines with their parental ones, we proved that radioresistant cell lines maintain expression of epithelial to mesenchymal associated genes, altered DNA repair machinery, and activated prosurvival signaling like PI3K/AKT. Our data also proves, in vivo, that blocking the chaperone HSP90 in combination with radiation therapy inhibits tumor growth and that HSP90 inhibition can abrogate the expression of cancer stem cells and epithelial to mesenchymal markers as seen by the reduction of b-catenin expression on treated xenografted tumors.