2023 Targeted Therapies of Lung Cancer Meeting (Poster)-P1.28. Inhibition of ATR Can Target Osimertinib Resistance in EGFR-Mutated NSCLC

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ATR inhibitors have the potential to target osimertinib resistance in non-small cell lung cancer (NSCLC) with EGFR mutations, according to research presented at the IASLC Targeted Therapies of Lung Cancer Meeting in 2023. Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is a common occurrence in NSCLC, and currently, there are no FDA-approved therapies for patients who develop resistance to TKIs other than chemotherapy. The study suggests that targeting the processes leading to resistance rather than specific resistance mechanisms may provide therapeutic opportunities.<br /><br />The researchers conducted a pilot study using in vitro-derived osimertinib-resistant cells and found that these cells exhibited increased evidence of DNA damage repair (DDR) activation and dependence on ATR and ATM, which are classical DDR effectors. They observed a linear relationship between osimertinib resistance and ATR sensitivity, indicating a mechanistic connection between the two.<br /><br />Further experiments showed that the osimertinib-resistant cells were sensitive to inhibitors of ATR and ATM, which are involved in single-strand break and double-strand break repair, respectively. However, no increase in sensitivity was observed for PARP inhibitors or platinum chemotherapy.<br /><br />Based on these findings, the researchers propose that ATR inhibitors could target EGFR-mutated NSCLC with osimertinib resistance by clearing out cells with a high mutation load, potentially leading to longer therapeutic effectiveness of EGFR TKIs and increased cell death with TKI treatment.<br /><br />In conclusion, this study suggests that ATR inhibitors have the potential to overcome osimertinib resistance in EGFR-mutated NSCLC. Further research is ongoing to better understand the relationship between osimertinib resistance and ATR dependence and to develop more specific therapies for this patient population.

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Benjamin Herzberg, Columbia University Medical Center, United States

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Speaker Benjamin Herzberg, Columbia University Medical Center, United States

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Keywords

ATR inhibitors

osimertinib resistance

non-small cell lung cancer

NSCLC

EGFR mutations

EGFR tyrosine kinase inhibitors

chemotherapy

DNA damage repair

ATR sensitivity

EGFR TKIs