MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Lung cancer is a leading cause of cancer mortality, necessitating novel therapeutic strategies.
• Loss-of-function mutations in ATM (Ataxia-Telangiectasia Mutated), a DNA damage response kinase, are prevalent in lung adenocarcinoma.
• Directly targeting ATM in cancer treatment presents significant challenges.

Purpose of the Study:

• To investigate the therapeutic potential of targeting MEK1/2 kinases in ATM-deficient lung cancer.
• To explore the mechanistic basis of synthetic lethality between ATM loss and MEK inhibition.
• To evaluate ATM mutational status as a predictive biomarker for MEK inhibitor efficacy.

Main Methods:

• Utilized in vitro and in vivo models of lung cancer with varying ATM and KRAS/BRAF mutational status.
• Administered MEK inhibitors, including trametinib, to assess drug sensitivity in different genetic contexts.
• Investigated the interplay between ATM, MEK/ERK, and AKT/mTOR signaling pathways.

Main Results:

• ATM loss-of-function confers synthetic lethality with MEK1/2 inhibitors, including trametinib.
• Lung cancer cells lacking ATM exhibit heightened sensitivity to MEK inhibition, both in vitro and in vivo.
• ATM deficiency disrupts crosstalk between MEK/ERK and AKT/mTOR survival pathways, sensitizing cells to MEK blockade.
• ATM loss enhances the efficacy of MEK inhibitors in KRAS- or BRAF-mutant lung cancer cells.

Conclusions:

• ATM loss-of-function represents a novel synthetic lethal vulnerability in lung cancer.
• ATM mutational status serves as a mechanistic biomarker for predicting response to MEK inhibitors.
• This discovery may broaden the clinical application of MEK inhibitors beyond BRAF/RAS-mutant tumors and improve patient stratification.