RX-3117-resistant A549 cells showed enhanced sensitivity to the PKMYT1 inhibitor lunresertib and its synergistic interaction with RX-3117, suggesting further studies, especially in patients with elevated PKMYT1 expression, which correlates with significantly reduced survival rates, as seen in public databases and corroborated by an internal cohort of NSCLC patients. Here, PKMYT1 is linked to non-small cell lung carcinoma.