Gao Research | Urologic Surgery | UC Davis Health

A major focus of his research has been elucidating the mechanisms underlying therapeutic resistance. His laboratory developed multiple resistant cell models to current therapies, including enzalutamide, abiraterone, darolutamide, taxanes, and olaparib, to investigate the molecular mechanisms driving resistance. One area of investigation is the role of intracrine androgens and AKR1C3 in mediating resistance to AR-targeted therapies, including enzalutamide and abiraterone. His findings demonstrated that AKR1C3 upregulation and enhanced intracrine androgen synthesis restore AR signaling under castrate conditions. Pharmacologic inhibition of AKR1C3 using NSAIDs or novel dual AR-variant/AKR1C3 inhibitors (LX-1) re-sensitizes resistant cells and xenografts to AR blockade. This work, highlighted in Nature Reviews Urology (2015), and advanced into clinical evaluation (NCT02935205), established AKR1C3 as a clinically actionable metabolic driver of resistance (Liu et al., Cancer Res. 2015; Liu et al., Mol Cancer Ther. 2017; Liu et al., Mol Cancer Ther. 2019; Ning et al., Cancer Res. 2024). Complementing this, his team identified niclosamide, a well-known anthelmintic, as a potent inhibitor of constitutively active AR splice variants, notably AR-V7. This finding revealed that niclosamide suppresses AR-V7 expression, restores enzalutamide response, and induces apoptosis in resistant models. This discovery, highlighted in Nature Reviews Urology (2014), has inspired ongoing clinical trials (NCT02807805, NCT02532114) testing niclosamide-based combination therapies for AR-variant–driven CRPC (Liu et al., Clin Cancer Res. 2014; Liu et al., Mol Cancer Ther. 2017).

Dr. Gao further delineated the NF-κB2/p52 signaling axis as a key transcriptional driver linking inflammation, metabolic reprogramming, and AR variant expression. His studies—among the most cited in Molecular Cancer Therapeutics—demonstrated that NF-κB2/p52 promotes AR-V7 expression and glycolytic adaptation, thereby conferring enzalutamide resistance (Nadiminty et al., Mol Cancer Ther. 2013; Nadiminty et al., Mol Cancer Ther. 2015). These findings illuminated an inflammatory–metabolic circuit amenable to therapeutic intervention. Expanding beyond hormonal resistance, Dr. Gao uncovered ABCB1-mediated drug efflux as a critical determinant of taxane resistance in CRPC. His laboratory showed that antiandrogens inhibit ABCB1 efflux activity and reverse docetaxel resistance (Nature Reviews Urology, 2015), providing mechanistic insight into cross-resistance between AR-targeted and chemotherapy agents (Zhu et al., Mol Cancer Ther. 2013; Zhu et al., Clin Cancer Res. 2015; Lombard et al., Mol Cancer Ther. 2017).

His more recent work extends these mechanistic insights to the DNA damage response and PARP inhibitor (PARPi) resistance, a central challenge in precision oncology for advanced prostate cancer. His team developed multiple olaparib-resistant models (LN-OlapR, 2B-OlapR) and discovered that resistant cells evade G2/M checkpoint arrest, tolerate persistent DNA damage, and enhance DNA repair capacity—defects that can be reversed by CDK1 inhibition, restoring olaparib sensitivity. Transcriptomic and metabolic profiling revealed that PARPi-resistant cells undergo profound mitochondrial reprogramming, characterized by enhanced oxidative phosphorylation, increased mitochondrial mass, and elevated ATP production driven by PINK1 and NDUFS4, key regulators of mitochondrial quality control and electron transport. Genetic or pharmacologic suppression of PINK1 or NDUFS4—using the novel niclosamide analog ARVib-7—disrupted mitochondrial respiration, induced ferroptotic stress, and re-sensitized resistant tumor cells to PARPi treatment. Collectively, these findings define mitochondrial metabolic rewiring as a major mechanism of PARPi resistance and uncover actionable therapeutic vulnerabilities to overcome treatment failure in advanced prostate cancer (Lombard et al., Mol Cancer Ther. 2022; Schaaf et al., Cancers. 2023, Cancer Res Comm. 2024, Mol Cancer Ther. 2025).

Most prostate cancer patients respond initially to androgen ablation and antiandrogen therapy. However, virtually all patients relapse due to the acquisition of androgen-independent tumor cells. Unfortunately, there is currently no effective treatment for men with androgen-independent prostate cancer. The molecular changes in prostate cancer cells that lead to androgen-independent growth are not completely understood. One of his research focuses on understanding intracellular signaling regulations in prostate cancer cells leading to androgen independence. His team has identified cytokines such as IL-6 and IL-4 as inducers of androgen-independent progression of prostate cancer cells. The roles of signaling pathways such as Stat3, Akt and NF-κB induced by IL-6 and IL-4 have been subsequently demonstrated in androgen receptor activation and progression of androgen- independent prostate cancer. In addition, his research focused on understanding interactions among individual signaling transduction pathways (cross-talk). He has made a novel finding that Stat3 activates NF-kB p100 processing involves CBP/p300-mediated acetylation (Nadiminty et al., PNAS. 2006). His lab found that both Stat3 activation and NF-kB p52 overexpression play critical roles in androgen-independent progression.

Bone is the frequent site of many types of cancer metastasis, including prostate cancer. Advanced prostate cancer is frequently accompanied by the development of unique bone metastases characterized as osteoblastic (bone forming). This results in significant complications, including bone pain, fractures and spinal-cord compression, as well as hemiparesis and it can lead to morbidity with no curable treatment. The high prevalence of osteoblastic bone metastases in prostate cancer involves the production of osteoblast-stimulating factors by prostate cancer cells. His lab has focused on identifying factors involved in prostate-induced osteoblasts. Several factors have been identified, including prostate-specific antigen (PSA). PSA is a serine protease uniquely produced by prostate cancer cells and is an important serological marker for prostate cancer. His team demonstrated that PSA in an inducer of osteoblast differentiation. Modulation of the expression of osteogenic genes and alteration of the balance between osteoprotegerin (OPG)-RANKL by PSA suggests that PSA produced by metastatic prostate cancer cells may participate in bone remodeling in favor of the development of osteoblastic metastases in the heterogeneous mixture of osteolytic and osteoblastic lesions (Nadiminty et al. Clin Cancer Res. 2006). These findings provide a molecular basis for understanding the high prevalence of osteoblastic bone metastases in prostate cancer.