Abstract 2631: Neuregulin-1 expression correlates with sensitivity to the PI3K inhibitor, GDC-0032, outside of PIK3CA mutations in head and neck cancer
Authors: Savage Heidi M. , O'Brien Carol , Yauch Bob , Settleman Jeff , Lackner Mark R. , Wilson Timothy R. 
Published: May 2015

The phosphoinositol-3-kinase (PI3K) signaling pathway is one of the most frequently activated pathways in oncogenesis, and controls critical cellular processes such as proliferation, transcription and survival. GDC 0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30 fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. The gene that encodes the p110 alpha isoform of PI3K, PIK3CA, is frequently mutated in breast, colorectal and endometrial cancers. Previously published data demonstrated that GDC-0032 has increased activity against PIK3CA mutant cancer cell lines (Olivero A. et al., DDT02-01, AACR 2013).

To determine if there are additional predictive biomarkers outside of PIK3CA mutations for sensitivity to GDC-0032, we profiled over 550 cell lines, encompassing 13 of the main cancer types, to increasing concentrations of GDC-0032. As expected, a small percentage of all tumor types responded to GDC-0032 and, were assessed, correlated strongly with PIK3CA mutations. Intriguingly, the majority of head and neck squamous cell cancer (HNSCC) cell lines showed an IC50 concentration of less than 1uM, suggesting that HNSCC cell lines may be particularly susceptible to PI3K inhibition. Molecular profiling identified that only 10% of the HNSCC cell lines had a mutation within PIK3CA, and no consistent copy number alterations were observed in receptor tyrosine kinases or PTEN. To investigate this observation further, we developed a ”PIK3CA activation” algorithm, by utilizing the mutant-selective property of GDC-0032, and calculated a ratio of GDC-0032 to GDC-0941, a pan PI3K inhibitor with reduced in vitro selectivity for PIK3CA mutations. Following a proof of principle experiment in breast cancer cells, a GDC-0941/GDC-0032 ratio of ≥4 enriched for breast cancer cells with mutant PIK3CA (11 out of 13 cell lines). Application of the algorithm, to our panel of HNSCC cell lines identified 10 out of 34 cell lines that had a GDC-0941/GDC-0032 ratio of ≥4, with only 1 of these cell lines being PIK3CA mutant. Further molecular characterization identified high mRNA expression of neuregulin-1, the ligand for HER3, in GDC-0032 cell lines with a GDC-0941/GDC-0032 ratio of ≥4, compared to cell lines with a ratio of &lt;4. Pharmacodynamic analysis of sensitive and refractory HNSCC cell lines demonstrated that GDC-0032 inhibited the phospho-AKT pathway in both groups of cell lines, but GDC-0032 only suppressed downstream phospo-S6 signaling in the sensitive cell lines.

In conclusion, high throughput cell line screening identified a “PIK3CA activated” subset of HNSCC cell lines that correlated with increased neuregulin-1 expression and corresponding sensitivity to GDC-0032, outside of PIK3CA mutations.

Citation Format: Heidi M. Savage, Carol O'Brien, Bob Yauch, Jeff Settleman, Mark R. Lackner, Timothy R. Wilson. Neuregulin-1 expression correlates with sensitivity to the PI3K inhibitor, GDC-0032, outside of PIK3CA mutations in head and neck cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2631. doi:10.1158/1538-7445.AM2014-2631