Rationale for Using Irreversible Epidermal Growth Factor Receptor Inhibitors in Combination with Phosphatidylinositol 3-Kinase Inhibitors for Advanced Head and Neck Squamous Cell Carcinoma

Abstract

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 phosphatidylinositol 3-kinase (PI3K) and epidermal growth factor receptor (EGFR) pathway genes are common, and small molecules targeting these pathways have shown modest effects as monotherapies in patients. Whereas emerging preclinical data support the combined use of PI3K and EGFR inhibitors in HNSCC, inhuman 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 a isoform-selective PI3K inhibitor HS-173 and irreversible EGFR/ERBB2 dual inhibitor afatinib in most 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, although irreversible ERBB inhibitors showed strong synergistic activity with HS-173 in our models, none of the reversible ERBB inhibitors were synergistic in our study. 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.

The let-7 family of microRNAs suppresses immune evasion in head and neck squamous cell carcinoma by promoting PD-L1 degradation

“…Head and neck squamous cell carcinoma (HNSCC) is a malignancy that is often manifested as a treatment-resistant tumor arising from the epithelium of the head and neck [1]. As one of the most common cancer around the world, HNSCC is a debilitating cancer with unfavorable patient outcomes and survival rates [2, 3]. In addition, HNSCC exerts a massive burden on the patients’ health and society [4].…”

Sparse Graph Regularization Non-Negative Matrix Factorization Based on Huber Loss Model for Cancer Data Analysis

“…ERBB2, commonly referred to as HER2, may be critical for enhancing the synergistic effect of PI3K inhibitors in HNSC patients (Michmerhuizen et al, 2019). It is generally believed that dysregulated ERBB2 signaling plays a key role in the development of pancreatic cancer (Lin et al, 2019).…”

Dacomitinib and gedatolisib in combination with fractionated radiation in head and neck cancer

“…Many studies have provided compelling pre-clinical evidence for the use of EGFR and PI3K pathway inhibitors to treat HNSCC [25,28,[51][52][53][54][55][56][57]. Several of these studies have explored the combination of agents targeting both pathways with success in vitro [25,28,51,53]. However, very few studies have investigated dual targeting of these pathways in combination with radiation which remains standard-of-care in primary HNSCC.…”