SUN-301 CAMKK2-Regulated Host Metabolism as a Driver of Prostate Cancer Progression and Linked Comorbidities

Abstract Disclosure: M.H. Bashir: None. T. Pulliam: None. M. Yan: None. R. DeSouza: None. J. Singh: None. P.K. Saha: None. J. Han: None. D.E. Frigo: None. Epidemiological studies suggest a link between obesity and prostate cancer progression. However, what obesity-linked factors drive disease progression remains poorly understood. Moreover, metabolic syndrome is a common comorbidity for prostate cancer patients and exacerbated by androgen receptor (AR)-targeted therapy, the standard of care for men with advanced disease. Here, we sought to elucidate the underlying mechanisms linking obesity to prostate cancer progression using high-fat diet (HFD) induced models of obesity and metabolic syndrome. Our previous studies found that ablation of Camkk2, an AR-regulated gene and driver of prostate cancer cell growth, in HFD-fed TRAMP mice impaired metastatic colonization and lowered circulating insulin levels improving insulin sensitivity. Surprisingly, Camkk2-intact murine prostate cancer cells exhibited impaired tumor growth when propagated in Camkk2-null syngeneic hosts, indicating cancer cell-extrinsic functions for CAMKK2 in prostate cancer that we hypothesized were mediated through the regulation of circulating insulin levels. In support of our hypothesis, syngeneic tumors grew markedly faster in obese mice with symptoms of metabolic syndrome including higher basal insulin levels relative to tumor propagated in lean mice fed a normal diet (ND). Switching mice to a ND from HFD just prior to tumor injection significantly decreased the tumor growth, while doing the reverse (ND to HFD just prior to injection) did not impact tumor growth, suggesting secondary effects of the HFD aided pathogenesis. In both scenarios, circulating insulin levels were the best predictor of tumor growth. In vitro, prostate cancer cell lines treated with serum from HFD mice showed accelerated proliferation, further suggesting the involvement of a circulating factor. Importantly, infusion of insulin into healthy lean mice was sufficient to increase syngeneic tumor growth. Taken together, our findings suggest that inhibition of tumor-extrinsic CAMKK2 functions can concurrently treat both prostate cancers and related comorbidities such as hyperinsulinemia, and thus, nominate CAMKK2 as an appealing new drug target. Presentation: Sunday, July 13, 2025