Elucidating Taxane treatment resistance in lethal prostate cancer

Abstract

Despite diagnostic and therapeutic advances, prostate cancer remains the most commonly diagnosed cancer in men, with over 1.2 million new cases worldwide and 20% of cancer-related deaths in men. While initial androgen deprivation therapy (ADT) leads to remission, this treatment invariably fails, and the cancer progresses to advanced castration resistant PCa (CRPC) and metastases. Taxane chemotherapy is an approved treatment for CRPC and disrupts tubulin polymerization dynamics, mitosis, and DNA integrity, driving tumour cells to cell death. Treatment with Taxanes improves survival and quality of life but many CRPC patients either do not respond and benefit from treatment or eventually develop Taxane resistance. Biomarkers identifying mCRPCs patients sensitive to Taxanes could have a major clinical impact and improve patient care as well as the identification of novel therapeutic strategies. The aim of this PhD was to identify, validate and clinically qualify predictive biomarkers of Taxane sensitivity while potentially identifying new therapeutic strategies to reverse, or prevent the generation of Taxane resistance in advanced prostate cancer. This aim was first investigated by thorough in vitro studies in Taxaneresistant and sensitive prostate cancer cell line models, including RNA/DNA studies, protein analysis as well as morphological analysis. A resistance mechanism in preclinical cell line models validated in prior investigations was identified as ABCB1, a well described Taxane resistance driver in vitro. While the upregulation of ABCB1 has been proven to cause Taxane resistance in cell cultures of various cancer types, an upregulation in PCa patients was not detected. Due to the discrepancy between cell line and patient data revealed during these studies, resistance and sensitivity mechanisms were further investigated in patient-derived ctDNA sequencing data from three randomized clinical trials. Crosscomparing these data with further in-house generated datasets led to the discovery of several significantly associated Taxane-sensitvity genes, which have been subsequently investigated and validated in vitro.