2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.02B.03 MALAT1 And NEAT1 Contribute to Adaptive Mutability in the Transition from Drug Tolerance to Drug Resistance in Lung Cancer

EP.02B.03 MALAT1 And NEAT1 Contribute to Adaptive Mutability in the Transition from Drug Tolerance to Drug Resistance in Lung Cancer

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The study investigates the role of two long non-coding RNAs (lncRNAs), MALAT1 and NEAT1, in the transition from drug tolerance to resistance in lung adenocarcinoma, particularly focusing on EGFR-mutant PC9 lung cancer cells treated with the inhibitor osimertinib. Drug-tolerant persisters (DTPs) often lead to relapse in cancer patients, as they enter a reversible dormant state and can obtain mutations leading to drug resistance, a process facilitated by adaptive mutability. This involves the downregulation of DNA repair pathways and the upregulation of mutagenic pathways. The aim was to explore how MALAT1 and NEAT1 contribute to this transition, given their established roles in regulating DNA damage responses.<br /><br />Findings revealed that MALAT1 and NEAT1 are enriched in DTPs and are overexpressed with osimertinib treatment. Knocking down these lncRNAs via antisense oligonucleotides did not synergize with osimertinib, although it did impair the persistence and survival of DTPs under continuous osimertinib treatment. Notably, MALAT1-knockdown reduced homologous recombination capacity but without synergy with osimertinib therapy. Knockdown further reduced proliferative capacity in long-term osimertinib-treated cells, suggesting a potential role in maintaining DTP survival.<br /><br />Despite three months of treatment leading to tolerance, cells remained sensitive upon re-challenge with osimertinib, demonstrating reversible drug tolerance. The study concludes that while MALAT1 and NEAT1 contribute to adaptive mutability and drug tolerance, their precise roles do not strongly synergize with targeted therapy to enhance drug resistance. These findings indicate that targeting these lncRNAs could potentially delay the onset of resistance in EGFR-mutant lung cancer, although further investigations are necessary to fully elucidate their roles and therapeutic potential.

Asset Subtitle

William Davis

Meta Tag

Speaker William Davis

Topic Tumor Biology – Preclinical Biology

Keywords

lncRNAs

MALAT1

NEAT1

lung adenocarcinoma

EGFR-mutant

osimertinib

drug tolerance

drug resistance

DNA repair pathways

adaptive mutability