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<p>There are currently no effective targeted therapies for BRAF-mutant metastatic melanoma patients with acquired resistance to approved BRAF and MEK inhibitors (BRAFi and MEKi), and very few ongoing clinical trials. Anti-apoptotic BCL2 family proteins promote de novo resistance to several therapies, including single-agent BRAFi in BRAF-mutant melanomas. In this study, in vivo testing of a large collection of patient-derived xenograft (PDX) models from melanoma patients with acquired resistance to BRAFi or BRAFi+MEKi shows that combining BCL2 inhibitors (BCL2i; navitoclax or venetoclax) with BRAFi+MEKi induces tumor regressions in a subset of these PDXs. High basal BCL2 predicts response whereas high basal MCL1 predicts resistance to this strategy. MCL1 overexpression studies functionally validate its role in resistance. Further, combining BRAFi+MEKi with an MCL1 inhibitor (MCL1i) counteracts resistance and interestingly decreases MCL1i-associated markers of cardiotoxicity. Together these studies identify potential personalized strategies to improve outcomes in this challenging patient population.</p>

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Personalized targeting of BCL2 family proteins overcomes acquired resistance to BRAF-MEK inhibitors in preclinical melanoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月26日

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  • Y.N. Vashisht Gopal,
  • Evelyn de Groot,
  • Kaley Loftin,
  • Barbara Knighton,
  • Debora Ledesma,
  • Courtney Hudgens,
  • Diana Shamsutdinova,
  • Mehboob Ali,
  • Zhenlin Ju,
  • Min Xiao,
  • Toshitha Kannan,
  • Gregory Fontenot,
  • Michael S. Nakazawa,
  • Monzy Thomas,
  • Khalida Wani,
  • Clifford Stephan,
  • Phyu P. Aung,
  • Lawrence N. Kwong,
  • Janos Roszik,
  • Rehan Akbani,
  • Andrew Kossenkov,
  • Vito W. Rebecca,
  • Ryan J. Sullivan,
  • Meenhard Herlyn,
  • Michael A. Davies

摘要

There are currently no effective targeted therapies for BRAF-mutant metastatic melanoma patients with acquired resistance to approved BRAF and MEK inhibitors (BRAFi and MEKi), and very few ongoing clinical trials. Anti-apoptotic BCL2 family proteins promote de novo resistance to several therapies, including single-agent BRAFi in BRAF-mutant melanomas. In this study, in vivo testing of a large collection of patient-derived xenograft (PDX) models from melanoma patients with acquired resistance to BRAFi or BRAFi+MEKi shows that combining BCL2 inhibitors (BCL2i; navitoclax or venetoclax) with BRAFi+MEKi induces tumor regressions in a subset of these PDXs. High basal BCL2 predicts response whereas high basal MCL1 predicts resistance to this strategy. MCL1 overexpression studies functionally validate its role in resistance. Further, combining BRAFi+MEKi with an MCL1 inhibitor (MCL1i) counteracts resistance and interestingly decreases MCL1i-associated markers of cardiotoxicity. Together these studies identify potential personalized strategies to improve outcomes in this challenging patient population.