Elevated RET expression enhances EGFR activation and mediates EGFR inhibitor resistance in head and neck squamous cell carcinoma.

Co-activation of EGFR by alternative receptor tyrosine kinases (RTKs) might mediate resistance to EGFR inhibition in head and neck squamous cell carcinoma (HNSCC). Here we found a novel mechanism to improve the efficacy of EGFR inhibitor erlotinib on HNSCC. Immunohistochemistry, western blot, cell migration and invasion assays, cell proliferation, cell cycle analysis and in vivo serial transplantation assays were used to evaluate the role of RET on HNSCC cells. The elevated levels of a rearranged during transfection (RET) are observed in HNSCC and that high levels of RET correlate with increased tumor size, advanced tumor stage and decreased overall survival rate. The HNSCC cell proliferation and invasion were inhibited by RET knockdown in vitro and in vivo. The inhibition of RET expression markedly reduced EGFR phosphorylation and downstream EGFR signaling. The inhibition of RET signaling significantly increased the sensitivity of HNSCC cells to the EGFR inhibitor erlotinib in both in vitro and in vivo models. Our results offer a preclinical proof-of-concept supporting a role for RET signaling inhibition in a targeted therapeutic approach to improve the efficacy of EGFR inhibition in HNSCC.

Lin C ，Lu W ，Ren Z ，Tang Y ，Zhang C ，Yang R ，Chen Y ，Cao W ，Wang L ，Wang X ，Ji T ... -  《-》

Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors.

The genomic alterations identified in head and neck squamous cell carcinoma (HNSCC) tumors have not resulted in any changes in clinical care, making the development of biomarker-driven targeted therapy for HNSCC a major translational gap in knowledge. To fill this gap, we used 59 molecularly characterized HNSCC cell lines and found that mutations of AJUBA, SMAD4 and RAS predicted sensitivity and resistance to treatment with inhibitors of polo-like kinase 1 (PLK1), checkpoint kinases 1 and 2, and WEE1. Inhibition or knockdown of PLK1 led to cell-cycle arrest at the G2/M transition and apoptosis in sensitive cell lines and decreased tumor growth in an orthotopic AJUBA-mutant HNSCC mouse model. AJUBA protein expression was undetectable in most AJUBA-mutant HNSCC cell lines, and total PLK1 and Bora protein expression were decreased. Exogenous expression of wild-type AJUBA in an AJUBA-mutant cell line partially rescued the phenotype of PLK1 inhibitor-induced apoptosis and decreased PLK1 substrate inhibition, suggesting a threshold effect in which higher drug doses are required to affect PLK1 substrate inhibition. PLK1 inhibition was an effective therapy for HNSCC in vitro and in vivo. However, biomarkers to guide such therapy are lacking. We identified AJUBA, SMAD4 and RAS mutations as potential candidate biomarkers of response of HNSCC to treatment with these mitotic inhibitors.

Zhang M ，Singh R ，Peng S ，Mazumdar T ，Sambandam V ，Shen L ，Tong P ，Li L ，Kalu NN ，Pickering CR ，Frederick M ，Myers JN ，Wang J ，Johnson FM ... -  《-》

A positive feedback loop involving EGFR/Akt/mTORC1 and IKK/NF-kB regulates head and neck squamous cell carcinoma proliferation.

Li Z ，Yang Z ，Passaniti A ，Lapidus RG ，Liu X ，Cullen KJ ，Dan HC ... -  《Oncotarget》

Dacomitinib, an irreversible Pan-ErbB inhibitor significantly abrogates growth in head and neck cancer models that exhibit low response to cetuximab.

Ather F ，Hamidi H ，Fejzo MS ，Letrent S ，Finn RS ，Kabbinavar F ，Head C ，Wong SG ... -  《PLoS One》

Preclinical modeling of EGFR inhibitor resistance in head and neck cancer.

Quesnelle KM ，Wheeler SE ，Ratay MK ，Grandis JR ... -  《-》