Introduction Despite the development of more effective chemotherapy regimens, pancreas ductal adenocarcinoma (PDAC) remains one of the deadliest gastrointestinal malignancies. With reliance on still decades old cytotoxic systemic therapies, new and innovative targets are needed. The voltage-gated potassium channel Kv1.3 is highly expressed in mitochondria (mito) and plays an integral role in cell proliferation and oncogenesis. The role of mitoKv1.3 in PDAC is not well known, however, we posit that mitoKv1.3 plays an important role in pancreatic cancer growth. We sought to evaluate tissue expression of mitoKv1.3 in resected PDAC, characterize its role in tumor proliferation, and evaluate tumor growth inhibition using novel inhibitors of mitoKv1.3, developed by our group (PCARBTP and PAPTP).
Methods Kv1.3 tissue expression was evaluated in resected human PDAC specimens using immunohistochemistry (IHC). Kv1.3 expression was then correlated with recurrence-free survival. An orthotopic pancreas tumor injection model (PAN02 cells injected into C57/BL6 mice) and pancreas cancer cell lines were used to test the Kv1.3 inhibitors' effect on tumor growth.
Results IHC evaluation of 36 human PDAC specimens for Kv1.3 showed that 11.1% had no expression, 33.3% low, 19.4% intermediate, and 36.1% high expression. Only 8.3% of normal pancreas specimens had expression of Kv1.3. Over a median follow up of 19.3 months, patients with intermediate/high tumor Kv.1.3 expression had worse recurrence free survival of 16.0 vs 20.9 months, p=0.05. Using an orthotopic mouse model, we examined tumor growth in the setting of treatment with specific mitoKv1.3 inhibitors. Seven days post tumor injection, mice were treated with inhibitors and found to have tumor reductions of 72% with PCARBTP and 67% by PAPTP. H&E staining at the time of sacrifice showed there was no significant reduction in body weight or toxicity to the heart, lung, liver, and kidney with mitoKv1.3 inhibitor treatment. We then examined the synergistic effect of mitoKv1.3 inhibitors with cytotoxic chemotherapies. Compared to untreated controls, treatment with gemcitabine/abraxane and PCARBTP or PAPTP resulted in an 89% and 71% reduction in tumor size, respectively. To examine resistance to mitoKv1.3 inhibitor treatment, we utilized an orthotopic tumor transplantation model. After treatment of mice with mitoKv1.3 inhibitors, the tumors were re-transplanted and subsequently treated with inhibitors again. This resulted in a tumor volume reduction of only 37% and 44% with PCARBTP and PAPTP, suggesting drug resistance was developed by the tumor.
Conclusion Kv1.3 was highly expressed in resected human PDAC tissue and overexpression was associated with worse recurrence free survival. The use of novel mitochondrial Kv1.3 inhibitors resulted in substantial reduction in tumor growth without resultant organ toxicity. Furthermore, combination of Kv1.3 inhibitors and cytotoxic chemotherapies resulted in ~90% reduction in tumor size. These data show that mitochondrial Kv1.3 is not only a potential prognostic biomarker but also a therapeutic target for pancreas cancer.
Citation Format: Weiwei Li, Gregory Wilson, Magdalena Bachmann, Jiang Wang, Michael Edwards, Ildiko Szabo, Erich Gulbins, Syed Ahmad, Sameer Patel. The role and mechanism of voltage-gated potassium channel, Kv1.3, in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2742.