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Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.<\/jats:p>","DOI":"10.1038\/s41419-021-04029-4","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T06:02:42Z","timestamp":1627365762000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer"],"prefix":"10.1038","volume":"12","author":[{"given":"Danielle S.","family":"Potter","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruochen","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Bhola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Bueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1993-9013","authenticated-orcid":false,"given":"Anthony","family":"Letai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"4029_CR1","unstructured":"American Cancer Society: Cancer Facts and Figures 2018. 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He is on the scientific advisory board of Flash Therapeutics, Dialectic Therapeutics, and Zentalis Therapeutics. The following are US Patents regarding BH3 profiling, owned by Dana-Farber: 10,393,733; 9,902,759; 9,856,303; 9,540,674; 8,221,966; 7,868,133. A.L. and P.B. are inventors on patent applications US20180128813A1, US20180120297A1 held\/submitted by Dana-Farber Cancer Institute that covers HTDBP.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Primary NSCLC tumors described in the manuscript were obtained after patients signed an informed consent approved by the Institutional Review Board (#98-063). All mice used in the manuscript were maintained within the DCFI animal facility and all experiments involving animals were conducted in accordance with the DFCI policy and animal protocol, reviewed and approved by the DFCI Institutional Animal Care and Use Committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"741"}}