Inhibition of ACK1 to Overcome Drug Resistance in Prostate Cancer
Posted July 20, 2018
Kiran Mahajan, Ph.D., H. Lee Moffitt Cancer Center & Research Institute, University of South Florida
Nupam Mahajan, Ph.D., H. Lee Moffitt Cancer Center & Research Institute, University of South Florida
The androgen receptor (AR) is a paramount player in both the initiation and progression of prostate cancer (PCa). Cancer cells initially respond to treatment with anti-androgen drugs, such as enzalutamide, but often become resistant and progress to a lethal state of disease called metastatic castration-resistant prostate cancer (mCRPC). For these types of patients whose PCa no longer responds to anti-androgen drugs, novel therapies are greatly needed. To develop new therapies, researchers have studies mechanisms of therapeutic resistance, and extensive studies have established that one way cancer cells can bypass the effect of anti-androgens is by substantially increasing AR levels, although this mechanism is not fully understood.
To identify a new therapeutic strategy to tackle this problem, a team of researchers led by Drs. Kiran Mahajan and Nupam Mahajan at the H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, looked for novel AR interacting partners and identified the protein ACK1, which is frequently upregulated in mCRPC. With support from FY11, FY12, and FY14 Exploration – Hypothesis Development Awards to both investigators, they found that ACK1 is recruited by AR to increase AR protein production even in the presence of enzalutamide through a novel histone H4 phosphorylation event called Tyrosine 88 phosphorylation. Realizing the significance of this observation, they developed a novel small molecule inhibitor called (R)-9bMS that targets ACK1 and showed that it suppresses AR and its variant AR-V7 expression culminating in inhibition of growth of enzalutamide-resistant tumors in mice.
The promotion of AR protein production in the presence of enzalutamide through ACK1-mediated histone phosphorylation is a new finding in PCa. More importantly, the new inhibitor, (R)-9bMS, that the research team has developed could become a new therapeutic modality, especially for those patients that are not initially responsive to enzalutamide or have developed resistance to it. The H. Lee Moffitt Cancer Center has patented this discovery and licensed this compound for its development as a cancer drug. It is expected that this compound will become available for early clinical trials in the next 1-2 years.
Mahajan K, Malla P2 Lawrence HR, et al. 2017. ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer Cell.
Mahajan K and Mahajan NP. 2015. ACK1/TNK2 tyrosine kinase: molecular signaling and evolving role in cancers. Oncogene.
Mahajan K, Coppola D, Rawal B, et al. 2012. Ack1-mediated androgen receptor phosphorylation modulates radiation resistance in castration-resistant prostate cancer. J Biol Chem.
Last updated Thursday, October 8, 2020