RT Journal Article
SR Electronic
T1 Rationale for using irreversible EGFR Inhibitors in combination with PI3K inhibitors for advanced Head and Neck Squamous Cell Carcinoma
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.115162
DO 10.1124/mol.118.115162
A1 Nicole L. Michmerhuizen
A1 Elizabeth Leonard
A1 Chloe Matovina
A1 Micah Harris
A1 Gabrielle Herbst
A1 Aditi Kulkarni
A1 Jingyi Zhai
A1 Hui Jiang
A1 Thomas E. Carey
A1 Chad Brenner
YR 2019
UL http://molpharm.aspetjournals.org/content/early/2019/03/11/mol.118.115162.abstract
AB Head and neck squamous cell carcinoma (HNSCC) is a common and debilitating form of cancer characterized by poor patient outcomes and low survival rates. In HNSCC, genetic aberrations in PI3K and EGFR pathway genes are common, and small molecules targeting these pathways have shown modest effects as monotherapies in patients. While emerging preclinical data support the combined use of PI3K and EGFR inhibitors in HNSCC, in-human studies have displayed limited clinical success so far. Here, we examined the responses of a large panel of patient-derived HNSCC cell lines to various combinations of PI3K and EGFR inhibitors, including EGFR agents with varying specificity and mechanistic characteristics. We confirmed the efficacy of PI3K and EGFR combination therapies, observing synergy with alpha isoform selective PI3K inhibitor HS-173 and irreversible EGFR/ErbB2 dual inhibitor afatinib in the majority of models tested. Surprisingly, however, our results demonstrated only modest improvement in response to HS-173 with reversible EGFR inhibitor gefitinib. This difference in efficacy was not explained by differences in ErbB target selectivity between afatinib and gefitinib; despite effectively disrupting ErbB2 phosphorylation, the addition of ErbB2 inhibitor CP-724714 failed to enhance the effect of HS-173 gefitinib dual-therapy. Accordingly, while irreversible ErbB inhibitors showed strong synergistic activity with HS-173 in our models, we observed that none of the reversible ErbB inhibitors were synergistic. Therefore, our results suggest that the ErbB inhibitor mechanism of action may be critical for enhanced synergy with PI3K inhibitors in HNSCC patients and motivate further preclinical studies for ErbB and PI3K combination therapies.