The emergence of drug resistance presents an important challenge in the treatment of cancer. Significant advancements had been made towards potent, targeted anti-cancer agents. However, patients ultimately develop resistance. There is a critical need to elucidate the molecular basis of cancer drug resistance to achieve durable survival benefits for patients. I will discuss my work related to prostate, lung, and pancreatic cancers.

Hyperactivation of androgen signaling causes prostate cancer (PC), which develops alternative growth-promoting mechanisms to give rise to neuroendocrine prostate cancer (NEPC), a treatment-resistant and highly lethal PC subtype. Chemotherapy and androgen deprivation therapy (ADT) are the cornerstones of PC treatments. However, nearly all NEPC patients eventually relapse and succumb to the disease months after treatment initiation. The underlying mechanism is not fully understood. Thus, understanding and targeting molecular mechanisms that promote NEPC fate and/or ADT resistance will potentially re-sensitize NEPC to existing therapies.

Our mechanistic studies revealed that ADT-resistant NEPC cells dramatically upregulate the proteasome protein, Proteasome Subunit Alpha 2 (PSMA2), in response to ADT. Pharmacological inhibition of PSMA2 re-sensitized NEPC to ADT. We hypothesize that PSMA2 promotes ADT resistance by sensitizing NEPC cells to residual (post-therapy) androgen. Specifically, PSMA2 antagonizes HSP90, which normally sequesters the androgen receptor (AR) in the cytoplasm away from its nuclear targets, resulting in accelerated AR nuclear translocation and robust overgrowth. Consistent with this hypothesis, our data show that PSMA2 blockade inhibits AR nuclear translocation and AR transcriptional targets, including NEPC fate markers. Further, PSMA2 blockade desensitized AR transcriptional output to androgen. Finally, PSMA2 blockade prolongs animal survival in a mouse model of NEPC.

Like PC, non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Despite the progress made in treatment modalities, the issue of therapy resistance still poses a considerable hurdle in the management of these malignancies. The etiology of resistance to molecularly targeted therapy in NSCLC frequently involves genetic mutations that trigger alternative signaling pathways. NSCLC patients harboring sensitizing mutations in the epidermal growth factor receptor EGFR (T790M, L578R) are treated with Osimertinib, a potent tyrosine kinase inhibitor (TKI). However, nearly all patients develop TKI resistance. The underlying mechanisms are not fully understood. We found that Hsa-miR-22-3p, Hsa-miR-184, and Let-7b-5p functionally converge on the WNT/bcatenin and mTOR/AKT signaling axes, known cancer therapy resistance signals. Targeting Hsa-miR-22-3p and Hsa-miR-184 desensitized EGFR-mutated (T790M, L578R) NSCLC cells to Osimertinib.

Lastly, we explore new opportunities to target cancer drug resistance. We show that a genetically engineered strain of Salmonella typhimurium (CRC2631) preferentially kills pancreatic cancer (PanC) cells harboring oncogenic KRAS. In addition to direct cancer cell killing, CRC2631 safely penetrates PanC tissues, stimulates T cells, and correspondingly reduces tumor burden in mouse models of KRAS PanC.

Our work highlights a potential to achieve re-sensitization of cancer patients to existing therapies, including immunotherapy.
 

Committee Members

Dr. Yves Chabu - Chair
Dr. Mark Hannink - Member
Dr. Elizabeth King - Member 
Dr. Laura Schulz - Member