Cancer drug resistance mechanisms
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Significant advances have been made toward developing potent agents that selectively target and kill cancer cells. However, achieving durable clinical benefits remains a significant challenge in the management of cancer patients. Some patients either fail to respond or quickly relapse due to intrinsic or acquired drug resistance, respectively. Elucidation of the molecular mechanisms of intrinsic and acquired cancer drug resistance will not only improve our understanding of cancer biology, but it will also lead to the development for therapeutic strategies for achieving sensitization of patients to existing therapy, resulting in broader and more durable clinical benefits for patients. I will discuss my work related to drug resistance in prostate, lung, and pancreatic cancers. In prostate cancer (PC), hyperactivation of androgen signaling gives rise to adenocarcinoma, which develop into a treatment-resistant and highly lethal PC subtype, neuroendocrine prostate cancer (NEPC). 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. Understanding and targeting molecular mechanisms that promote NEPC fate transformation and/or NEPC resistance to ADT, will potentially re-sensitize PC to existing therapies. We found that the proteosome protein PSMA2 plays a dual role in PC resistance to ADT: on the one hand, treatment induced PSMA2 sensitizes PC cells to residual androgen, thereby limiting the efficacy of hormone therapy. We propose that ectopic PSMA2 achieves this effect by sequestering HSP90 away from the androgen receptor (AR), thereby enabling rapid AR nuclear translocation and activity. Consistent with this model, ADT-induced PSMA2 antagonizes AR-HSP90 protein complex formation and stimulate the expression of AR target genes. On the other hand, PSMA2 pushes prostate adenocarcinoma into NEPC fate transformation trajectory. Pharmacological inhibition of PSMA2 sensitizes these untreatable PC cells to ADT. In support of our findings PSMA2 blockade dramatically prolongs animal survival in a mouse model of NEPC. Treatment resistance is not unique to prostate cancer or hormone-targeted therapy; it is a ubiquitous challenge in oncology, as evidenced by the transient response of lung cancer patients to targeted therapy. Below I discuss our work on Non-small cell lung cancer (NSCLC) in the context of resistance to epidermal growth factor receptor (EGFR)-directed therapy. NSCLC accounts for a significant proportion of lung cancer cases, and EGFR-directed therapy has emerged as a targeted treatment option for patients with specific genetic mutations. However, resistance to this therapy often develops, ultimately limiting its long-term effectiveness and highlighting the need for novel strategies to overcome or circumvent resistance mechanisms. The widespread nature of resistance across various cancer types underscores the urgency of identifying innovative approaches to improve patient outcomes and ensure the durability of therapeutic responses. 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 plasma extracellular vesicles (EV) and circulating microRNAs fundamentally modulate cancer cell response to Osimertinib. Circulating Hsa-miR-22-3p and EV Hsa-miR- 184 and Let-7b-5p are deregulated in NSCLC patients. These miRNAs functionally converge on the WNT/ [beta]-catenin 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. In addition to inevitable acquired drug resistance, targeted agents benefit only limited subsets of patients because of their allele-dependent mechanisms of action. There is a need for a shift in cancer targeting paradigm to achieve broad and durable benefits for patients. Below I discuss our efforts toward the development of a bacteria-based biologic to target cancers broadly and durably. I focus on Pancreatic cancer (PanC). Oncogenic KRAS mutations are the primary drivers in 98 percent of pancreatic cancers. KRAS-driven cancers are highly desmoplastic and immuno suppressive. Desmoplastic pancreatic tumors impede drug delivery, leading to inadequate intratumoral concentrations of the targeted agents and immune exclusion, rendering these tumors resistant to immunotherapy. KRAS-targeted approaches are being actively pursued to overcome the physical and immune barriers of pancreatic cancers. Oncogenic mutations in the KRAS gene occur at specific codons (12, 13, and 61). Existing KRAS directed agents (Sotorasib, Adagrasib) selectively target the KRAS(V12C), which account only for 1-2 percent of pancreatic cancers. Further, patients eligible for these agents develop robust resistance, limiting the long-term benefits for this treatment modality. Furthermore, efforts to combine KRAS(V12C) directed agents with checkpoint immunotherapy reveal significant toxicity. We show that a genetically engineered strain of Salmonella typhimurium (CRC2631) safely penetrates PanC tissues, stimulates effector 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.
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Ph. D.