Loss of Pol ζ was the strongest scoring synthetic lethal interaction after POLD2 and ATR. NSCLC and TNBC cells depleted of the catalytic subunit, REV3, showed synthetic lethality with ATRi alone and marked synergy with ATRi/cisplatin treatment in every cell line tested, further validating our observation. Here, POLD2 is linked to non-small cell lung carcinoma.