PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Non-small cell lung cancer (NSCLC) treatment faces challenges, particularly in patients with specific genetic alterations.
• The tumor suppressor PTEN is frequently mutated in NSCLC, correlating with resistance to various cancer therapies.
• PTEN-deficient tumors exhibit inherent resistance to radiation, chemotherapy, and immunotherapy.

Purpose of the Study:

• To investigate the mechanisms underlying therapy resistance in PTEN-deficient NSCLC.
• To identify potential therapeutic vulnerabilities in PTEN-mutated NSCLC.
• To evaluate the efficacy of targeting specific DNA damage response pathways in combination with radiation therapy.

Main Methods:

• Analysis of transcriptional programs in PTEN-deficient tumor cells.
• Assessment of DNA damage response pathways, including ATM and ATR, during ionizing radiation (IR).
• Pharmacological inhibition of ATM using KU-60019 and AZD1390 in vitro and ex vivo models.

Main Results:

• Loss of PTEN alters transcriptional programs, leading to radiation resistance.
• PTEN-deficient cells rely on ATM, but not DNA-PK or ATR, for resistance to IR.
• ATM inhibition, at non-toxic doses, restores sensitivity to IR and synergizes with IR in PTEN-deficient NSCLC models.

Conclusions:

• PTEN-deficient NSCLC tumors are dependent on ATM for DNA damage repair following radiation.
• Targeting ATM represents a potential therapeutic strategy to overcome IR resistance in PTEN-mutated NSCLC.
• Low-dose ATM inhibitors can synergize with IR to treat PTEN-deficient NSCLC in preclinical models.