The phosphoinositol-3-kinase (PI3K) signaling pathway is one of the most frequently activated pathways in cancer, and controls critical cellular processes such as proliferation, transcription and survival. Taselisib (GDC0032) is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Previously published data demonstrated that taselisib has increased activity against PIK3CA mutant cancer cell lines (Ndubaku CO et al, J Med Chem, 2013).

A panel of 50 breast cancer cell lines were profiled for sensitivity to taselisib using viability assays and subsequently correlated with PIK3CA mutations and expression of ER, PR, HER2 and PTEN. The PIK3CA mutant cell lines displayed an average of 30-fold greater sensitivity in IC50 compared to the PIK3CA wild-type cell lines. PTEN null cell lines were largely refractory to taselisib. Within the PIK3CA wild-type cell lines, the HER2 amplified cells showed an average of 18-fold greater sensitivity in IC50 over the HER2 wild-type cell lines. No differences in taselisib sensitivity were seen between the kinase, helical, or the C2 domain of the PIK3CA gene within the PIK3CA mutant cell lines. In HER2 amplified PIK3CA wild-type cell lines, taselisib did not fully suppress pAKT and pS6 signaling, however full suppression was observed in combination with the HER2 inhibitor, lapatinib. Increased apoptosis was observed with the combination of taselisib and lapatinib in the HER2 amplified, PIK3CA mutant cells, but not in HER2 amplified, PIK3CA wild-type cells. In PIK3CA mutant luminal cell lines, taselisib induced ESR1 transcriptional activity, but not in PIK3CA wild-type luminal lines, as assessed using PR, GREB1 and IGFBP4 gene expression. This induction was ER- and estradiol-dependent, and was suppressed using the estrogen degrader, fulvestrant. Lastly, as up to 40% of ER+, second line PIK3CA mutant metastatic tumors have been shown to harbor a mutation in the ESR1 gene (Spoerke JM et al., Nat Commun, 2016), we assessed the crosstalk between the PI3K and ER pathways in PIK3CA mutant MCF-7 cells that overexpress two ESR1 hotspot mutations. These ESR1 mutant cell lines displayed increased ER transcriptional activity, which was further activated by taselisib, an observation that was reversed with fulvestrant co-treatment. These data suggest that the combination of taselisib and an estrogen degrader can suppress crosstalk between PI3K and ER in both an ESR1 mutant and wild-type background, and supports the ongoing SANDPIPER study of taselisib in combination with fulvestrant in metastatic ER+, PIK3CA mutant cancers that have progressed following an aromatase inhibitor therapy (NCT02340221).

Citation Format: Heidi M. Savage, Heather M. Moore, Carol L. O'Brien, Wei Zhou, Ciara Metcalfe, Mark R. Lackner, Timothy R. Wilson. Identifying preclinical predictive biomarkers to taselisib in breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1780. doi:10.1158/1538-7445.AM2017-1780