ArticleThe Journal of clinical investigation2017
Dual modulation of MCL-1 and mTOR determines the response to sunitinib.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 57 citations in OpenAlex.
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- Exploiting artificial intelligence in precision oncology: an updated comprehensive review.Journal of translational medicine · 2025Review
- Translational regulation of SND1 governs endothelial homeostasis during stress.The Journal of clinical investigation · 2025Article
- Interleukin 6 and cancer resistance in glioblastoma multiforme.Neurosurgical review · 2024Review
- Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- Oxygen tension-dependent variability in the cancer cell kinome impacts signaling pathways and response to targeted therapies.iScience · 2024Article
- PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer.Frontiers in oncology · 2024Article
- Ubiquitin-proteasome pathway-mediated regulation of the Bcl-2 family: effects and therapeutic approaches.Haematologica · 2024Review
- Cabozantinib in neuroendocrine tumors: tackling drug activity and resistance mechanisms.Endocrine-related cancer · 2023Article
- USP9X mediates an acute adaptive response to MAPK suppression in pancreatic cancer but creates multiple actionable therapeutic vulnerabilities.Cell reports. Medicine · 2023Article
- Review
- ID proteins promote the survival and primed-to-naive transition of human embryonic stem cells through TCF3-mediated transcription.Cell death & disease · 2022Article
- Raman and fluorescence micro-spectroscopy applied for the monitoring of sunitinib-loaded porous silicon nanocontainers in cardiac cells.Frontiers in pharmacology · 2022Article
- Article
- Article
- MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia.Frontiers in cell and developmental biology · 2021Article
- Sunitinib facilitates metastatic breast cancer spreading by inducing endothelial cell senescence.Breast cancer research : BCR · 2020Article
- Tuning mTORC1 activity dictates the response of acute myeloid leukemia to LSD1 inhibition.Haematologica · 2020Article
- HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models.The Journal of clinical investigation · 2020Article
- Increased autophagy/mitophagy levels in primary tumours of patients with pancreatic neuroendocrine neoplasms.Endocrine · 2020Article
Corrections and comments
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Authors and funding
20 authors at 10 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.
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