Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

Adaptation of cancer cells to targeted therapy follows ecological paradigms observed in natural populations that encounter resource depletion and changing environments, including activation of pro-survival mechanisms, migration to new locations, and escape of predation. We identified the p38 MAPK pathway as a common molecular driver of these three responses during the adaptation to hormone therapy resistance in prostate cancer. The p38 pathway is activated in therapy-resistant cells and mechanistically drives these three convergent responses through sustained AR activity, enhanced invasion and metastasis, and immune evasion. Targeting p38 signaling may represent a new therapeutic strategy to treat men with metastatic, hormone therapy-resistant prostate cancer. ### Competing Interest Statement AJA receives consulting income and research support to Duke from Pfizer/Astellas, Bayer, Dendreon, Merck, AstraZeneca, and Janssen. He receives research support to Duke from BMS, Constellation, Gilead, Genentech/Roche. MP and EP are inventors on US Government and University assigned patents and patent applications that cover aspects of the technologies discussed such as Reverse Phase Protein Microarrays. As inventors, they are entitled to receive royalties as provided by US Law and George Mason University policy. MP and EP receive royalties from Avant Diagnostics. EP is consultant to and shareholder of Avant Diagnostics, Inc and Perthera, Inc. All other authors declare no competing interests.