OVERRIDING CISPLATIN RESISTANCE IN LUNG SQUAMOUS CELL CARCINOMA: INSIGHTS FROM COMBINATION WITH HDAC INHIBITOR

Abstract

LUNG CANCER REMAINS A LEADING CAUSE OF CANCER-RELATED MORTALITY. IN RECENT YEARS, GENOMIC ANALYSES OF LUNG ADENOCARCINOMA HAVE YIELDED SIGNIFICANT STRATEGIES AGAINST PATHWAY ACTIVATION TO IMPROVE TREATMENT, BUT THESE EFFORTS HAVE BEEN LESS SUCCESSFUL IN LUNG SQUAMOUS CELL CARCINOMA (SCC). IN THIS STUDY, NEXT GENERATION SEQUENCING TECHNOLOGY CONFIRMED A PAUCITY OF ONCOGENIC DRIVER LESIONS IN LUNG SCC. CELL LINES WITH INHERENT RESISTANCE TO CISPLATIN WERE FIRST IDENTIFIED. DRUG-INDUCED PERTURBATIONS TO GENE AND PROTEIN EXPRESSION WERE BEING COMPARED. ACTIVATION OF MAPK/ERK PATHWAY WAS SHOWN TO CONFER CISPLATIN RESISTANCE, WHILE MEK INHIBITORS AND BELINOSTAT AUGMENTED CISPLATIN SENSITIVITY IN SCC CELLS THROUGH INHIBITION OF MAPK/ERK SIGNALLING. PARALLEL INVESTIGATIONS SHOWED THAT BELINOSTAT POTENTIATED CISPLATIN-INDUCED APOPTOSIS IN SCC CELLS HARBOURING TP53 MUTATION. THIS CELL DEATH MECHANISM WAS DEMONSTRATED TO BE A GAIN-OF-FUNCTION EVENT IN P53 MUTANT CELLS. IN SUMMARY, THIS THESIS PRO