Figure 1 from Camonsertib, an ATRi, in Combination with Low-Dose Gemcitabine in Solid Tumors with DNA Damage Response Aberrations: Preclinical and Phase Ib Results

Preclinical data: combination of low doses of camonsertib and gemcitabine. A, Cell viability (as measured by CTG) of RPE1 TP53-KO ATM-WT or ATM-KO cells after indicated treatments. B, In vitro, low doses of camonsertib and gemcitabine elicit sensitivity in ATM-deficient cells. ZIP combination scores in RPE1 TP53-KO ATM-WT or ATM-KO cells treated with indicated concentrations of cam and gemcitabine and processed for a CTG viability assay are shown. C, In vitro, low doses of camonsertib and gemcitabine elicit cytotoxicity in BRCA1-deficient cells. Viability of SUM149PT cells (BRCA1-mutant triple-negative breast carcinoma) as measured by a CTG growth assay. Cells were either left untreated or treated with 4 hours of gemcitabine, day 1, 2, or 3 of camonsertib, or combined camonsertib and gemcitabine. Compounds were then washed out, and viability was measured on day 8. D, Mice bearing Granta-519 tumors were treated with camonsertib (3/4 days weekly) or gemcitabine (once weekly) as single agents and in combination at the indicated doses. Tumor growth is represented as the mean ± SEM; n = 8 mice/group. Statistical differences between groups were determined using an unpaired t test with Welch correction. ***, P < 0.001; ****, P < 0.0001 (Prism v10.4). At termination of the experiment, complete blood counts were taken from all mice. E, Mean RBC, F, neutrophils, and G, platelets are shown ±SEM. Dashed lines represent normal range for age-, sex-, and strain-matched mice. Statistical differences were determined using one way ANOVA and Fisher LSD test (Prism v10.4). ns, not significant; *, P < 0.05; ****, P < 0.0001. Abbreviations: CTG, CellTiter-Glo; LSD, least significant difference; Max, maximum; PO, per-oral; QD, once daily; QW, once weekly; RBC, red blood cell.