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<p>The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. <i>KRAS</i>-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor <i>STK11/</i>LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient <i>KRAS</i>-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient <i>KRAS-</i>mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.</p>

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LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月2日

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  • Chendi Li,
  • Mohammed Usman Syed,
  • Anahita Nimbalkar,
  • Yi Shen,
  • Melissa D. Vieira,
  • Cameron Fraser,
  • Zintis Inde,
  • Xingping Qin,
  • Jian Ouyang,
  • Johannes Kreuzer,
  • Sarah E. Clark,
  • Grace Kelley,
  • Emily M. Hensley,
  • Robert Morris,
  • Raul Lazaro,
  • Brian Belmonte,
  • Audris Oh,
  • Makeba Walcott,
  • Christopher S. Nabel,
  • Sean Caenepeel,
  • Anne Y. Saiki,
  • Karen Rex,
  • J. Russell Lipford,
  • Rebecca S. Heist,
  • Jessica J. Lin,
  • Wilhelm Haas,
  • Kristopher Sarosiek,
  • Paul E. Hughes,
  • Aaron N. Hata

摘要

The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.