Loss of MAP3K7 and CHD1 Expression Drive Recurrence, Resistance in Prostate Cancer

By Marilynn Larkin

April 26, 2021

NEW YORK (Reuters Health) - Loss of MAP3K7 protein expression, seen in approximately 40% of prostate cancer patients, is a major driver of prostate tumor aggressiveness and should be considered for inclusion in management algorithms, researchers say.

Loss of MAP3K7 also predicts biochemical relapse and, along with loss of CHD1, confers resistance to anti-androgen therapy, their new data show.

"The MAP3K7 gene encodes TGF-beta activated kinase 1 (TAK1), a serine-threonine kinase in the MAP kinase super family that is involved in sensing stress responses in the cell," Dr. Scott Cramer of the University of Colorado Anschutz Medical Campus in Aurora explained in an email to Reuters Health.

"We showed that loss of MAP3K7 expression in prostate cancer cell models leads to castrate-resistant growth in hormone therapy-naive cells," he said. "Its loss also confers resistance to the anti-androgen enzalutamide. We also showed that loss of MAP3K7 protein expression is a significant independent predictor of biochemical relapse in a well-controlled patient cohort."

"Loss of MAP3K7...should be considered as a marker to be included in predictive algorithms designed to strategy patients for therapeutic options," he continued. "Current algorithms have not included MAP3K7 status in their models."

As reported in Molecular Cancer Research, Dr. Cramer and colleagues conducted a series of preclinical experiments with prostate cancer cell line models engineered to cosuppress MAP3K7 and CHD1, and analyzed selected cases from the Stanford University database of surgically removed prostates (1986-2003), matching 112 cases with biochemical recurrence and 94 without.

They found, as Dr. Cramer noted, that loss of MAP3K7 and CHD1 increased androgen receptor (AR) gene expression, altered chromatin binding and increased enzalutamide resistance.

They also found that while CHD1 loss mainly affects AR cistrome expansion, loss of MAP3K7 drives increased AR target gene expression.

Further, the analysis of radical prostatectomy specimens showed that MAP3K7, in particular, was the strongest independent predictor of biochemical recurrence risk among several tested factors, including CHD1 expression.

Dr. Cramer added, "These studies suggest that patients with prostate tumors that have lost MAP3K7 expression might be poor candidates for anti-androgen therapy and may need alternative therapeutic interventions to control disease progression. A study by our group in 2019 (https://bit.ly/3tEDu2i) showed that loss of MAP3K7 confers synergistic sensitivity to CDK2 inhibitors and PARP inhibitors, suggesting a possible intervention strategy."

Dr. Murugesan Manoharan, Chief of Urologic Oncology at Baptist Health's Miami Cancer Institute in Florida, commented by email to Reuters Health that the findings "need to be validated in other studies and other centers (and) verified in real-world clinical practice. Once findings are confirmed, the assessment of these gene losses can become part of clinical workup and management of prostate cancer."

SOURCE: https://bit.ly/3dHNrqj Molecular Cancer Research, online April 12, 2021.