BACKGROUND. EGFR and
Src family kinases are upregulated in
head and neck squamous cell carcinoma (
HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in
HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor,
erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify
biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa
HNSCC were randomized to 7-21 days of neoadjuvant
erlotinib, the Src inhibitor
dasatinib, the combination of both, or placebo. Paired
tumor specimens were collected before and
after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase
protein array of tissue lysates. Candidate
biomarkers were assessed for correlation with change in
tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in
tumor size in both
erlotinib arms (P = 0.0014); however, no effect was seen with
dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to
erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to
dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to
erlotinib significantly decreased
tumor size in operable
HNSCC, with no additive effect from
dasatinib. Baseline pMAPK expression warrants further study as a response
biomarker for anti-EGFR
therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of
dasatinib in
biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for
Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.