Role of ER stress-driven IRE1α-XBP1 Signaling in Lung Cancer Pathogenesis

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Abstract Mutant KRAS driven non-small cell lung cancer (NSCLC), confer a dismal 5-year survival rate of only 15-20%. Despite this clinical significance, there is a lack of an effective targeted therapy for the treatment of KRAS lung cancer. Given this unmet clinical need, my goal is to investigate the endoplasmic reticulum (ER) stress response, particularly the protumorigenic IRE1α-XBP1 signaling pathway as an untapped resource of novel targets for therapy development. The protumorigenic role of ER stress response is being explored in various tumor types. However, this pathway had not been investigated properly in lung cancer. To first establish the clinical relevance, I analyzed a tissue microarray of >300 NSCLC clinical samples, and showed activated XBP1 in both the cancer and the stromal cells. Consistent with these observations, XBP-1 activation was observed in both the cancer cells and in the intratumoral dendritic cells, associated with activation of downstream genes in mutant Kras, p53-/- preclinical model of lung cancer. These preliminary findings, have led to the hypothesis that the aberrant IRE1α- XBP1signaling axis may contribute to carcinogenesis. Using genetic approaches (CRISPR/RNAi), and compartment-restricted recombinase systems (Clec9a-Cre or CD11c-Cre), I will investigate the cell-specific roles of IRE1α-XBP1 signaling in tumor growth, metastatic capacity and survival. Perturbation of IRE1α/XBP-1 in tumor-infiltrating DCs will be used to assess their role in T-cell-mediated anti-tumor immunity, as this may provide key insights into whether XBP-1 targeting would enhance the efficacy of immune checkpoint blockade inhibitors. Finally, the therapeutic potential of targeting the IRE-1-XBP1 pathway in NSCLC will be accomplished using selective pharmacological inhibitors of IRE1α. This study has a potential to yield targets of prognostic and therapeutic value in the IRE-1-XBP1 pathway in KRAS lung cancer, which represents >30% of lung adenocarcinomas.