CMSA Interdisciplinary Science Seminar: Molecular mechanisms of Taxane resistance in prostate cancer
Fang Xie - Harvard Medical School
Taxanes act by stabilizing microtubules (MTs) and prolong survival in men with prostate cancer (PCa), but biomarkers predictive of responses and clinically actionable mechanism(s) of resistance have yet to be identified. We recently reported that a decrease or absence of MT bundling, despite high levels of intratumoral taxanes, is a basis and a potential pharmacodynamic biomarker of taxane resistance. To determine the molecular basis for this impaired MT bundling, we treated docetaxel sensitive PCa models in vivo for multiple cycles until resistance, and found upregulation of FOXJ1 (a master transcription factor regulating tubulin associated proteins), as well as one of its downstream effector protein, TPPP3, in the resistant tumors. Moreover, mining of patient databases showed that amplification of the FOXJ1 gene is also associated with taxane exposure. Together these data implicate the FOXJ1-TPPP3 regulatory network in taxane resistance. In parallel with these in vivo studies, we have carried in vitro drug screens for agents that enhance responses to docetaxel in 3D/organoid culture. A prominent agent that emerged is a histone methyltransferase inhibitor. Our overall goals are to identify clinically meaningful mechanisms of taxane resistance, to develop therapeutic combinations that enhance efficacy and/or target these resistance mechanisms, and to identify biomarkers indicative of specific mechanisms. Our hypotheses, which are based on our published and preliminary data, are that one major mechanism for taxane resistance is upregulation of the FOXJ1-TPPP3 pathway, and that combination therapies can be developed that enhance taxane efficacy and delay or prevent the emergence of resistance. The specific aims are 1) Determine the effect of FOXJ1-TPPP3 regulatory network on microtubule dynamics, stability and target-engagement by taxanes in vitro and in vivo and 2) Identify effective combination therapies to enhance docetaxel responses and overcome taxane resistance.