Enhanced synergy of pacritinib with temsirolimus and sunitinib in preclinical renal cell carcinoma model by targeting JAK2/STAT pathway

Abstract

Pacritinib is an oral medication that inhibits several kinases including JAK2, FLT3, IRAK and STAT3. It has been recently approved to treat patients with thrombocytopenia and myelofibrosis. Studies are currently exploring the potential use of pacritinib in treating other types of cancer such as leukaemia, breast cancer and prostate cancer. Our study aimed to investigate the effects of pacritinib alone and its combination with standard of care in renal cell carcinoma (RCC). We showed that pacritinib dose-dependently decreased viability of RCC cells, with IC₅₀ at nanomolar or low micromolar concentration rage. Pacritinib inhibited cell proliferation, decreased colony formation, and increased apoptosis. Interestingly, pacritinib exhibited synergistic effects when combined with temsirolimus and sunitinib, but antagonistic effects when combined with doxorubicin, in a panel of RCC cell lines. We also confirmed that the combination of pacritinib with temsirolimus and sunitinib resulted in synergistic effects in RCC mouse models, with complete inhibition of tumour growth throughout the treatment period. Mechanistic studies indicated that the inhibition of JAK2, but not IRAK, was the main contributor to the anti-RCC activity of pacritinib. Our study is the first to demonstrate that pacritinib shows promise as a treatment option for RCC and underscores the therapeutic potential of targeting the JAK2/STAT signalling pathway in RCC.

Keywords:

• Pacritinib
• temsirolimus
• doxorubicin
• sunitinib
• JAK2/STAT
• RCC

Authors’ contributions

LL and YT designed and supervised the study, FM and LG performed the experiments, FM, LG and LL interpreted the data, YT wrote the manuscript. All authors revised the manuscript and approved the final version.

Availability of data and materials

Data available within the article.

Disclosure statement

No potential conflict of interest was reported by the author(s)

Informed consent

Not applicable

Research involving human participants and/or animals

The Institutional Animal Care and Use Committee of Xiangyang No.1 People’s Hospital granted approval for this study (Approval number XYYYE20220099). All procedures conducted adhered to the ethical standards set forth by the 1964 Helsinki declaration and its subsequent amendments, or equivalent ethical guidelines.

Additional information

Funding

This work was supported by a research grant provided by the Health and Family Planning Commission of Hubei Province (WJ2017M232).