Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes
- Kathryn E. Ware ,
- Santosh Gupta ,
- Jared Eng ,
- Gabor Kemeny ,
- Bhairavy J. Puviindran ,
- Wen-Chi Foo ,
- Lorin Crawford ,
- R. Garland Almquist ,
- Daniella Runyambo ,
- Beatrice C. Thomas ,
- Maya U. Sheth ,
- Anika Agarwal ,
- Mariaelena Pierobon ,
- Emanuel F. Petricoin ,
- David L. Corcoran ,
- Jennifer Freedman ,
- Steven R. Patierno ,
- Tian Zhang ,
- Simon Gregory ,
- Zoi Sychev ,
- Justin M. Drake ,
- Andrew J. Armstrong ,
- Jason A. Somarelli
bioRxiv |
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.