AI Article Synopsis
- Small-cell lung cancer (SCLC) is a very dangerous type of lung cancer that doesn't usually respond well to standard treatments.
- A new drug called lurbinectedin was recently approved for patients whose cancer came back, but doctors think using it with other treatments might work better.
- Researchers found that combining lurbinectedin with a special drug called berzosertib may help more patients by making cancer cells grow uncontrollably and die, and they are now testing this combination in a clinical trial.
Article Abstract
Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405061 | PMC |
| http://dx.doi.org/10.15252/emmm.202217313 | DOI Listing |
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