William Pao M.D., Ph.D.

Recipient of the Barbara Parisi Lung Cancer Research Grant.

Lay Description

Lung cancer is responsible for more cancer-related deaths in the U.S. and worldwide each year than any other cancer. Most patients with metastatic disease are treated with empirically chosen conventional chemotherapies. However, two small molecules, Iressa and Tarceva, have been approved for use in metastatic non-small cell lung cancer (NSCLC); both drugs are classified as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), because they selectively block signaling from the EGFR protein. Mutations in the gene encoding EGFR are associated with sensitivity of tumors to these agents. Unfortunately, most patients whose tumors initially respond to these drugs eventually develop progression of disease. We and others have shown that in some patients with such “acquired resistance," tumors contain a second site mutation in the EGFR gene after disease progression. This mutation leads to a change in an amino acid in the protein (threonine to methionine at position 790 or “T790M”) which is predicted to block binding of either Iressa or Tarceva to EGFR. Whether NSCLC patients who develop such resistance to Iressa or Tarceva can be treated with other targeted agents is unknown. Furthermore, mechanisms underlying secondary resistance in the remainder of cases remain to be elucidated.

The overall goal of this proposal is to use human tumor specimens, preclinical lung tumor models, and various molecular and biochemical techniques to enhance knowledge about the subset of cancers that develop acquired resistance to Iressa and Tarceva. We aim to: 1) characterize further potential mechanisms of acquired resistance which are still dependent upon signaling through EGFR by analyzing the status of the EGFR gene in tumor tissue from more patients (up to 80 individuals) initially sensitive to Iressa or Tarceva, and establish how any newly identified changes (i.e. mutations) in the EGFR gene affect biochemical properties of EGFR, such as signaling activity and sensitivity to EGFR TKIs; 2) characterize preclinical models carrying inducible transgenes that encode the common T790M resistance mutation by itself and in the context of a drug-sensitive EGFR mutation (called “L858R”), comparing them to models that express the drug-sensitive EGFR mutation (L858R) alone; and 3) identify targeted agents and strategies to overcome acquired resistance to Iressa or Tarceva. Ultimately, we hope to use the knowledge gained from our studies to determine the most effective way to both treat progressive disease and suppress the development of acquired resistance in human patients.

Scientific Abstract

In virtually all non-small-cell lung cancer (NSCLC) patients who exhibit dramatic responses to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib (Iressa), or erlotinib (Tarceva), the disease eventually progresses. Recently, we and others have shown that 4 of 7 patients with such “acquired resistance” contain tumors with a second mutation in the EGFR kinase domain after progression, in addition to primary drug-sensitive EGFR mutations. From crystal structure analyses, the resulting amino acid change (T790M) is predicted to block binding of drug to the ATP pocket via steric clash resulting from introduction of the bulky methionine residue. Whether NSCLC patients who develop T790M-mediated resistance to gefitinib or erlotinib can be treated with other targeted agents is unknown. Furthermore, mechanisms underlying secondary resistance in the remainder of cases remain to be elucidated.

The overall goal of this project is to identify clinically relevant mechanisms of acquired resistance to gefitinib and erlotinib and to begin testing strategies to overcome acquired resistance. Specifically, we aim to: 1) determine the changes in EGFR sequence or copy number that occur on treatment failure in more patients (up to 80 individuals) initially sensitive to gefitinib or erlotinib, and establish how newly “acquired” mutations affect biochemical properties of EGFR, such as kinase activity and sensitivity to EGFR TKIs; 2) characterize transgenicmodels  carrying tetracycline-inducible transgenes that encode the common T790M resistance mutation by itself and in the context of a drug-sensitive EGFR mutation (L858R), comparing them to models that express the drug-sensitive EGFR mutation (L858R) alone; and 3) identify targeted agents and strategies to overcome acquired resistance to gefitinib or erlotinib. Ultimately, we hope to determine the most effective way of integrating new strategies into the clinic to both treat progressive disease and suppress the development of acquired resistance.