The focus of my research is to understand mechanisms of sensitivity and resistance to kinase inhibitors and to translate laboratory based observations into therapeutic treatments for patients with cancer. To achieve this goal we have taken a multifaceted approach; combining cell biological and biochemical studies with genomic studies of human tumors from patients treated with kinase inhibitors.

We have extensively studied the epidermal growth factor receptor (EGFR) and its therapeutic relevance in non-small cell lung cancer (NSCLC). EGFR targeted therapies are an effective treatment for subsets of patients with NSCLC and our studies have centered on understanding the genomic and biochemical bases underlying their clinical effectiveness.

Our laboratory was among the first to identity somatic mutations in EGFR and their association with the exquisite in vitro sensitivity and dramatic clinical tumor regressions in NSCLC patients treated with EGFR tyrosine kinase inhibitors. The current focus of our laboratory include 1.) understanding signaling mechanisms in EGFR mutant cancers 2.) delineating the in vitro and clinical significance of different types of EGFR mutations 3.) identifying and investigating the efficacy of different classes of EGFR inhibitors in EGFR mutant cancers and 4.) identifying resistance mechanisms to EGFR targeted therapies and using the findings to develop novel therapeutic strategies. We have also extended analogous studies to therapeutic EGFR antibodies that are used in the treatment of head and neck and colorectal cancers. Furthermore we are studying other kinases including MET or ALK that are activated by genomic mechanisms in lung and other cancers. In order to translate our preclinical studies into clinical treatments and to evaluate their efficacy in lung cancer patients, we are actively developing translational tools (such as sensitive genotyping or FISH analyses) to help guide this process.

The overarching goal of our studies is to identify subsets of cancers where specific kinase inhibitors may be effective treatments and to use these findings for the basis for rationale clinical trial design. Importantly our work on EGFR mutations and on specific resistance mechanisms has already led to series of clinical trials for patients with lung cancer.