Abstract
Introduction: PI3K pathway, in addition to its pro-proliferative and anti-apoptotic effects on tumor cells, is known to contribute to DNA-damage repair (DDR). We hypothesized that GDC-0980, a dual PI3K-mTOR inhibitor, will induce an efficient anti-tumor effect in BRCA-competent PTEN-null TNBC cells when combined with PARP inhibitor, ABT888 and carboplatin. We propose that in PTEN-null BRCA-competent TNBC model, the growth of TNBC tumor will be blocked due to the inhibition of (1) HR and NHEJ and (2) PI3K-mTOR pathway mediated survival signals following treatment with GDC-0980, when combined with PARP inhibitor (impaired DNA-SSB-repair) and carboplatin (increased DNA-DSB). Purpose: Here we tested the efficacy of a combination of GDC-0980 with ABT888 plus carboplatin in BRCA-competent PTEN-null model of TNBC. Methods: Athymic mice bearing PTEN-null TNBC xenograft tumors were treated with GDC-0980 alone or in combination with ABT888 and carboplatin. Results: Dual inhibition of PI3K and mTOR by GDC-0980 alone as well as in the presence of carboplatin plus ABT888 changed the state of the repair of DNA-damage in BRCA-competent PTEN null TNBC cells, which led to increased cellular apoptotic signals in addition to decreased survival/proliferative signals. GDC-0980 treatment led to DNA damage (increased pgH2AX), gain in PAR and a subsequent sensitization of BRCA-competent PTEN-null MDA-MB468 TNBC cells to ABT888 plus carboplatin with a time-dependent (1) decrease in proliferation signals (pAKT T308/S473, pP70S6K, pS6RP), PAR/PARP ratios, PAR/pgH2AX ratios, live/dead cell ratios, cell-cycle progression and clonogenic 3D growth and (2) increase in apoptosis markers (cleaved-caspase 3, 9, BIM, cleaved-PARP and annexinV positivity). These effects are more pronounced in MDA-MB468 than in RAS/RAF mutated MDA-MB231 cells. GDC-0980 alone and in combination with ABT888 plus carboplatin inhibited cell cycle progression, increased apoptosis, and decreased live/dead cell ratios in BRCA-competent PTEN null TNBC cells. GDC-0980 alone and in combination with ABT888 plus carboplatin attenuated anchorage -dependent and -independent clonogenic 3D growth comparatively more in BRCA-competent PTEN-null cells TNBC cells than MDA-MB231 cells. GDC-0980 in combination with ABT888 plus carboplatin blocked the growth of established PTEN-null TNBC tumors as compared to vehicle control(s) with a concomitant decrease in tumor Ki67 and CD31 IHC-stains. Conclusion: This is the first mechanism-based study to demonstrate that in BRCA-competent PTEN-null TNBC model, GDC-0980 enhanced antitumor activity of ABT888, in the presence of carboplatin by inhibiting DDR system in conjunction with the inhibition of PI3K-mTOR pathway-mediated proliferative, and anti-apoptotic signals. Considering (1) the importance of PARP as the target in TNBC, (2) the existence of a large percentage of BRCA-competent TN and/or basal type BC patients and (3) the high frequency of PTEN-null-ness in this subset of BC, this combination merits further investigation.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-04-02.
Volume 73, Issue 24 Supplement
