Determining mechanisms of resistance to next-generation EGFR inhibitors

2013

Therapeutics Award

Lecia V. Sequist, MD

Massachusetts General Hospital

Boston

Jeffrey Engelman, MD, PhD

Massachusetts General Hospital

Boston

Joel Neal, MD, PhD

Stanford University

Stanford

Dr. Sequist will develop models that explain how NSCLC patients can acquire drug resistance to targeted therapies after a period of initial successful treatment, leading to the development of new treatments to help patients overcome the drug resistance.

Research Summary

One of the biggest advances in lung cancer therapy has been the development of genotype-directed therapy, where patients can be tested to see which genes are the most active in their cancers and then targeted pills can be given to shut down the messages sent from those genes. This type of treatment has been extremely successful for lung cancer patients whose cancers are EGFR mutation; however, resistance to the EGFR targeted therapy develops after about one year. The focus of our research is how drug resistance occurs and how to prevent it.

Our group at Mass General has led a large effort to understand how cancers become resistant to anti-EGFR therapy by biopsying patients who have become drug resistant and testing their tumors with real-time molecular and genetic analyses to tell us what is driving cancer growth. Our research proposal extends this work broader and deeper, looking at the mechanisms of drug resistance to the newest EGFR therapies currently entering the clinic with a next-generation deep sequencing platform. In addition, we will derive individual, patient-specific laboratory models of the resistant cancers from the material gathered at the biopsy. These models will facilitate functional research into the biology of the resistant cancers and screening with broad panels of targeted therapies to inform doctors what the best therapy options may be for an individual patient in their practice.

Our patient-oriented study will leverage bi-directional knowledge exchange between the bench and the bedside and across institutions to gain insight into how lung cancers acquire resistance to the next generation of EGFR therapies, in turn directing patients to the most appropriate treatment strategy to overcome resistance.

Technical Abstract

The genotype-directed use of EGFR TKIs in EGFR-mutant lung cancer patients has fundamentally changed the face of the disease with improved response to therapy, preserved quality of life, and prolonged progression-free survival. However, tumors that initially respond become resistant after ~ 1 year (i.e., acquired resistance, AR). The biology of AR is incompletely understood and is largely inferred from pre-clinical models. Our group at Mass General implemented a wide-scale program to perform repeat biopsies on EGFR-mutant patients with AR to first-generation EGFR inhibitors (gefitinib, erlotinib). This translational research paradigm has been instrumental in gaining insight into AR and has led to novel observations such as PIK3CA and BRAF mutations as mechanisms of AR and the abundant frequency of phenotypic changes at the time of AR like small cell lung cancer and epithelial-to-mesenchymal transitions. The repeat biopsy results have directly helped our patients as well, by informing choices about the most relevant clinical trials or alternative treatments. Currently, a new cohort of EGFR TKIs is entering the clinic: 2^nd-generation irreversible pan-HER inhibitors and 3^rd-generation T790M-specific inhibitors. Little is known about how AR develops to these newer therapies or how the biology of EGFR-mutant cancers evolves over time after exposure to sequential EGFR blockers.

Our proposal aims to discover the mechanisms of AR to next-generation EGFR TKIs and to understand the evolution of EGFR-mutant cancers as they face the selective pressure of sequential types of EGFR-directed therapies. To accomplish this we will collaborate across institutions to amass a large number of pre-treatment and post-treatment paired patient biopsies which we will interrogate via allele-specific genotyping as well as whole genome sequencing to define mechanisms of AR. In addition we will utilize an innovative technique of taking tumor tissue directly from a biopsy and deriving patient-specific in vitro and in vivo models in the laboratory. Expansion of these models will yield a larger supply of AR cancer material to aid descriptive and functional research about the biology of AR. In addition, establishment of pre-treatment patient-specific models will allow us to verify whether the mechanism of AR derived in the lab through ex-vivo therapy mirrors the eventual clinical mode of AR.

Key words

Acquired resistance

Adenocarcinoma

Biomarker or biomarker testing

Epidermal growth factor receptor (EGFR)

Non-small cell lung cancer (NSCLC)

Stage III

Stage IV

Targeted therapy

Tyrosine kinase inhibitors (TKIs)

Determining mechanisms of resistance to next-generation EGFR inhibitors

LUNGevity Foundation

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