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23.02.2024 | Research

Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma

verfasst von: Tingyu Liu, Xin Yue, Xue Chen, Ru Yan, Chong Wu, Yunzhi Li, Xianzhang Bu, Hui Han, Ran-Yi Liu

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Abstract

Purpose

Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application.

Methods

We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc.

Results

From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect.

Conclusion

Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically.

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Titel: Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma
verfasst von: Tingyu Liu
Xin Yue
Xue Chen
Ru Yan
Chong Wu
Yunzhi Li
Xianzhang Bu
Hui Han
Ran-Yi Liu
Publikationsdatum: 23.02.2024
Verlag: Springer Netherlands
Erschienen in: Cellular Oncology
Print ISSN: 2211-3428
Elektronische ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-024-00927-9

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Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma

Abstract

Purpose

Methods

Results

Conclusion

Neu im Fachgebiet Pathologie

Assistierter Suizid durch Infusion von Thiopental

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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Neu im Fachgebiet Pathologie

Assistierter Suizid durch Infusion von Thiopental

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren