Inhibition of PI3K/BMX cell survival pathway sensitizes to BH3 mimetics in SCLC.
AuthorsPotter, Danielle S
Hodgkinson, Cassandra L
Blackhall, Fiona H
Morrow, Christopher J
AffiliationClinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester
MetadataShow full item record
AbstractMost small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo These data add to a body of evidence that this combination should move toward the clinic. Mol Cancer Ther; 15(6); 1248-60. ©2016 AACR.
CitationInhibition of PI3K/BMX cell survival pathway sensitizes to BH3 mimetics in SCLC. 2016, 15 (6):1248-60 Mol Cancer Ther
JournalMolecular Cancer Therapeutics
- Rapamycin rescues ABT-737 efficacy in small cell lung cancer.
- Authors: Gardner EE, Connis N, Poirier JT, Cope L, Dobromilskaya I, Gallia GL, Rudin CM, Hann CL
- Issue date: 2014 May 15
- BMX acts downstream of PI3K to promote colorectal cancer cell survival and pathway inhibition sensitizes to the BH3 mimetic ABT-737.
- Authors: Potter DS, Kelly P, Denneny O, Juvin V, Stephens LR, Dive C, Morrow CJ
- Issue date: 2014 Feb
- HSP90 inhibitor (NVP-AUY922) enhances the anti-cancer effect of BCL-2 inhibitor (ABT-737) in small cell lung cancer expressing BCL-2.
- Authors: Yang H, Lee MH, Park I, Jeon H, Choi J, Seo S, Kim SW, Koh GY, Park KS, Lee DH
- Issue date: 2017 Dec 28
- Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer.
- Authors: Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM
- Issue date: 2008 Apr 1
- Combination treatment with ABT-737 and chloroquine in preclinical models of small cell lung cancer.
- Authors: Zinn RL, Gardner EE, Dobromilskaya I, Murphy S, Marchionni L, Hann CL, Rudin CM
- Issue date: 2013 Mar 2