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조회397

박상현Sanghyun Park

전남대학교 의과대학, KAIST

Exp. Mol. Med., Apr 16 2024, | https://doi.org/10.1038/s12276-024-01210-5 Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation

Sanghyun Park^1,2,6, Won-Ji Ryu^3,6, Tae Yeong Kim³, Yumi Hwang³, Hyun Ju Han³, Jeong Dong Lee³, Gun Min Kim⁴, Joohyuk Sohn⁴, Sang Kyum Kim⁵, Min Hwan Kim⁴ and Joon Kim²

¹Department of Dermatology, Chonnam National University Medical School, Gwangju, Korea.

²Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.

³Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, Korea.

⁴Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

⁵Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.

⁶These authors contributed equally: Sanghyun Park, Won-Ji Ryu.

Corresponding authors : Correspondence to Sang Kyum Kim, Min Hwan Kim or Joon Kim.

Abstract

Transcriptional programs governed by YAP play key roles in conferring resistance to various molecular-targeted anticancer agents. Strategies aimed at inhibiting YAP activity have garnered substantial interest as a means to overcome drug resistance. However, despite extensive research into the canonical Hippo-YAP pathway, few clinical agents are currently available to counteract YAP-associated drug resistance. Here, we present a novel mechanism of YAP stability regulation by MAP3K3 that is independent of Hippo kinases. Furthermore, we identified MAP3K3 as a target for overcoming anticancer drug resistance. Depletion of MAP3K3 led to a substantial reduction in the YAP protein level in melanoma and breast cancer cells. Mass spectrometry analysis revealed that MAP3K3 phosphorylates YAP at serine 405. This MAP3K3-mediated phosphorylation event hindered the binding of the E3 ubiquitin ligase FBXW7 to YAP, thereby preventing its p62-mediated lysosomal degradation. Robust YAP activation was observed in CDK4/6 inhibitor-resistant luminal breast cancer cells. Knockdown or pharmacological inhibition of MAP3K3 effectively suppressed YAP activity and restored CDK4/6 inhibitor sensitivity. Similarly, elevated MAP3K3 expression supported the prosurvival activity of YAP in BRAF inhibitor-resistant melanoma cells. Inhibition of MAP3K3 decreased YAP-dependent cell proliferation and successfully restored BRAF inhibitor sensitivity. In conclusion, our study reveals a previously unrecognized mechanism for the regulation of YAP stability, suggesting MAP3K3 inhibition as a promising strategy for overcoming resistance to CDK4/6 and BRAF inhibitors in cancer treatment.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-16)
연구진국내 연구진
분야 의약학 > 분자세포의학

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