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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Co-occurring mutations can limit targeted therapy efficacy in cancer.
• KRAS-mutant lung cancers often exhibit loss of the STK11/LKB1 tumor suppressor.
• The role of LKB1 in cellular stress response to therapy is not well understood.

Purpose of the Study:

• To investigate the role of LKB1 in regulating cellular responses to KRAS-targeted therapy.
• To identify therapeutic vulnerabilities in LKB1-deficient KRAS-mutant lung cancers.

Main Methods:

• Utilized LKB1-deficient KRAS-mutant lung cancer cell models.
• Investigated the effects of KRAS or MEK inhibition on JNK signaling.
• Assessed apoptotic dependencies and vulnerability to BCL-XL and MCL-1 inhibitors.

Main Results:

• KRAS or MEK inhibition in LKB1-deficient cells led to JNK hyperactivation via loss of NUAK-mediated PP1B activity.
• JNK-mediated phosphorylation of BCL-XL altered apoptotic pathways.
• LKB1-deficient cells became sensitive to MCL-1 inhibition.

Conclusions:

• LKB1 regulates stress signaling and mitochondrial apoptosis independently of its AMPK/SIK tumor suppressor functions.
• A novel, genotype-informed therapeutic vulnerability in LKB1-deficient KRAS-mutant lung cancers was identified.
• This vulnerability can potentially enhance the efficacy of KRAS-targeted therapies.