Capivasertib (AZD5363) plus AZD5991 combination activity in endometrial cell lines. A, Screening results of combo Emax versus HSA in endometrial cell lines treated with AZD5363 plus AZD5991. Cell lines with high combination activity are in red. B, Representative growth inhibition and HSA excess matrix plots in endometrial AN3CA cells. C, Matrix plot measuring apoptosis with AZD5991 and AZD5363 at indicated doses for 6 hours in AN3-CA cells. D, Matrix plots showing viability for AN3-CA cells pretreated with DMSO or QVD (caspase inhibitor) for 16 hours prior to the combination for 6 hours. E, Western blot analysis in AN3-CA cells treated with AZD5363 (1 μmol/L), AZD5991 (500 nmol/L), or in combination at indicated times. F, Matrix plots showing viability in AN3-CA cells treated with AZD5991 or venetoclax (ABT-199 -BCL2 inhibitor), AZD4320 or AZ3202 (BCL-XL inhibitors) with AZD5363 at indicated doses for 6 hours.
ARTICLE ABSTRACT
Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific “emergent” biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets.
We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of “emergent” combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses.This article is featured in Selected Articles from This Issue, p. 695
