Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have poor efficacy in head and neck squamous cell carcinoma (HNSCC). Because the insulin-like growth factor-1 receptor (IGF1R) generates potent prosurvival signals and has been implicated in therapeutic resistance, its ability to induce resistance to EGFR-TKIs was studied in vitro. Five HNSCC cell lines demonstrated reduced sensitivity to the EGFR-TKI gefitinib when the IGF1R was activated. In SCC-25 and Cal27 cells, gefitinib inhibited basal and EGF-stimulated EGFR, Erk and Akt phosphorylation and reduced cell number. This correlated with initiation of apoptosis based on a 4-fold increase poly-(ADP-ribose) polymerase (PARP) cleavage and a 2.5-fold increase in Annexin V positivity. The apoptotic response and reduction in cell number were blocked by IGF1R activation, which resulted in phosphorylation of both Erk and Akt. In both cell lines, IGF1R-induced Erk but not Akt activation was eliminated by gefitinib. IGF1R-induced gefitinib resistance was unaffected by MEK inhibition with U0126, but was partially impaired by inhibition of phosphatidylinositol 3′-kinase (PI3K) with LY294002. The IGF1R-TKI PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib. Thus the IGF1R can make HNSCC cells resistant to EGFR-TKI treatment via a prosurvival mechanism. Of 8 studied, all HNSCC tumor samples expressed the IGF1R and 5 demonstrated detectable IGF1R phosphorylation, suggesting that this receptor may be relevant in vivo, and thus combined EGFR/IGF1R inhibition may be necessary in some patients for effective targeted molecular therapy.

Background Although oral squamous cell carcinomas (OSCCs) commonly overexpress the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) exhibit poor efficacy clinically. Activation of the IGF1R induces resistance of OSCC cells to EGFR-TKIs in vitro. This study seeks to evaluate the changes in cell cycle status in OSCC cells in response to gefitinib and IGF1R activation. Methods SCC-25 OSCC cells were used for in vitro analyses. Results Gefitinib caused a 50% reduction in S-phase population and IGF1R activation caused a 2.8-fold increase; combined treatment yielded a baseline S-phase population. Gefitinib treatment increased the cyclin-dependent kinase inhibitor p27 and this was not abrogated by IGF1R activation. pT157-p27 was noted by immunoblot to be decreased on gefitinib treatment, but this was reversed with IGF1R activation. T157 phosphorylation contributes to cytoplasmic localization of p27 where it can promote cell proliferation and cell motility. Using both subcellular fractionation and immunofluorescence microscopy techniques, IGF1R stimulation was noted to increase the relative cytoplasmic localization of p27; this persisted when combined with gefitinib. Conclusions IGF1R activation partially reverses the cell cycle arrest caused by gefitinib in OSCC cells. While IGF1R stimulation does not eliminate the gefitinib-induced increase in total p27, its phosphorylation state and subcellular localization are altered. This may contribute to the ability of the IGF1R to rescue OSCC cells from EGFR-TKI treatment and may have important implications for the use of p27 as a biomarker of cell cycle arrest and response to therapy.

IMPORTANCE Complications of partial flap necrosis contribute substantially to morbidity in patients who undergo head and neck reconstructive surgery. OBJECTIVE To assess the usefulness of clinical findings, intraoperative fluorescein angiography, and intraoperative indocyanine green angiography (ICGA) for evaluation of flap skin paddle perfusion in patients undergoing oromandibular reconstruction who are at high risk of partial skin paddle necrosis. DESIGN, SETTING, AND PARTICIPANTS Retrospective medical record review from May 21, 1996, to May 27, 2015, at a tertiary care academic medical center. Participants were 73 patients who underwent reconstruction of through-and-through defects of the mucosa, mandible, and skin using fibula free flaps that contained large bilobed skin paddles. MAIN OUTCOMES AND MEASURESThe rates of partial skin paddle necrosis and revision reconstructive surgery. RESULTSThe rates of partial flap necrosis were 8% (n = 2) among 25 patients in whom the skin paddle was trimmed based on ICGA and 33% (n = 16) among 48 patients in whom the skin paddle was trimmed according to clinical findings (P = .02). The rates of revision reconstructive surgery were 20% (5 of 25) when flap skin paddles were trimmed using ICGA and 42% (20 of 48) when trimmed per clinical findings (P = .06). CONCLUSIONS AND RELEVANCEThe use of ICGA may reduce the risk of partial skin flap necrosis in free flaps used in patients undergoing head and neck reconstruction who are at high risk of developing flap necrosis. Indocyanine green angiography imaging should be considered in any flap in which skin paddle viability is uncertain based on clinical findings and in patients in whom the skin paddle extends beyond the primary and adjacent angiosomes. LEVEL OF EVIDENCE 3.

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