Background: Therapeutic blockade of Epidermal Growth Factor Receptor (EGFR) signaling with the monoclonal antibody cetuximab is clinically effective in the treatment of patients with metastatic squamous cell carcinoma of the head and neck or KRAS wildtype colorectal cancer. However, these patients eventually become resistant to this therapy. An exploration of the EGFR signaling network using an EGFR network-focused small interfering RNA library identified potential regulators of resistance to EGFR-targeted therapies. The ABL1 gene was identified as a central node to target in this complex genomic pathway. In a preclinical EGFR-expressing cancer cell line model, targeting c-abl, the gene product of ABL1, using nilotinib was found to be highly synergistic in decreasing cell survival when combined with anti-EGFR targeted therapy. Methods: We have initiated an open-label Phase I study for patients who progressed after standard therapies for metastatic KRAS wildtype colorectal cancer or metastatic head and neck squamous cell carcinoma. Enrolled patients must have adequate performance status and organ function. Treatment consists of cetuximab 400 mg/m² on day 1, then 250 mg/m² once weekly, and nilotinib twice daily, starting on day 1, according to a traditional 3+3 dose escalation, from 200mg to 300mg BID. Patients are restaged every 2 cycles (every 8 weeks). The primary endpoint is the maximum tolerated dose (MTD) of nilotinib when used in conjunction with cetuximab. Secondary endpoints are clinical benefit rate (defined as rates of stable disease, partial response, and complete response) and response rate. Additionally, biopsies of metastases obtained prior to and after initiation of therapy will be used to establish primary tumor cell cultures using conditional cellular reprogramming to permit the dynamic study of signaling and drug sensitivity through an evaluation of evidence of a drug effect on EGFR signaling and on Antibody-Dependent Cell-Mediated Cytotoxicity. An additional 10 colorectal cancer patients will be treated as an expansion cohort at the MTD. This expansion cohort data may be used to plan a Phase II trial in the future.