Susumu Kobayashi M.D., Ph.D.

Recipient of the Joan’s Legacy/Michael R. Pascucci Lung Cancer Association Grant. Funded equally by Joan's Legacy and the Michael R. Pascucci Lung Cancer Association.

Lay Description

Lung cancer is the leading cause of cancer deaths in the United States, and approximately 20% of cases occur in never smokers. Recently, it has become clear that never smokers with non-small cell lung cancer (NSCLC) have tumor alterations that differ from their smoker counterparts. The first gene mutation clearly linked to this group of patients includes mutations in the EGFR gene; a protein that once mutated can lead to lung cancer and therefore called an oncogene. With time, other genetic abnormalities have been identified in never smokers with NSCLC. The most recent finding was the identification of a fusion gene between EML4 and ALK. This fused protein, EML4-ALK, acts as an oncogene as well. In the past 30 years, chemotherapy-based treatment of lung cancer has not significantly improved outcome of this deadly disease. However, in EGFR mutated patients the use of orally available drugs that target the EGFR receptor (called EGFR tyrosine kinase inhibitors [TKIs]) has led to dramatic and often prolonged responses. For EML4-ALK NSCLC, novel ALK TKIs have entered clinical trials and some of these new drugs have show similar benefits to those seen in EGFR mutated NSCLC treated with EGFR TKIs. Despite impressive results with this class of TKIs, most tumors eventually become resistance to continued drug exposure. In the case of EGFR mutated tumors in less than a year, in average, most tumors develop frank resistance to the two commonly used EGFR TKIs (gefitinib and erlotinib). Our group and others have been at the forefront of identifying mechanisms of resistance to EGFR TKIs, and we now know that resistance mutations or activation of other oncogenes explains the majority of cases of resistance in these specific tumors. It is tempting to speculate that similar mechanisms of resistance will also occur in EML4-ALK NSCLC treated with ALK TKIs. Therefore, this study will try to compile and understand the mechanisms of resistance of EML4-ALK NSCLC to novel ALK TKIs that are entering clinical studies. These studies will help understand how these tumors escape inhibition by the drugs that are targeted against them, and this knowledge will eventually help the development of new treatments for EML4-ALK NSCLC.

Scientific Abstract

Approximately 20% of non-small cell lung cancers (NSCLCs) in the United States occur in never smokers, and never smoker-related NSCLC ranks among the top 10 deadliest cancers worldwide. Mutations in EGFR are present in almost half of never smokers with NSCLC. These mutations are oncogenic and predict for response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. After the identification of EGFR mutations in 2004, an immense effort was put forth to identify other clinically relevant oncogene alterations in NSCLC. We now know that KRAS, ErbB2 mutations and the EML4-ALK inversion are also present in NSCLC, and these genetic oncogene abnormalities are more frequent in adenocarcinomas and in never smokers. “Oncogene addicted” tumors (i.e. EGFR and EML4-ALK NSCLC) are prone to develop acquired resistance to TKIs, and identification of the mechanisms of resistance (mutations or oncogene “kinase switches”) may help identify novel therapies to overcome these TKI-resistant tumors. This project will attempt to compile a comprehensive analysis of the resistance mechanisms of EML4-ALK NSCLC to ALK-specific TKIs. Aim I will attempt to identify the mechanisms of resistance of EML4-ALK NSCLC to ALK kinase inhibitors by studying cell line models of resistance as well as samples of patients being treated with a the novel ALK TKI PF2341066. Aim II will investigate a novel ALK deletion identified in a patient sample as a mechanism of resistance to ALK TKIs. We will also investigate the molecular mechanisms underlying development of the mutation. These studies will lead to new insights into EML4-ALK-driven tumorigenesis, as well as the improvement of ALK targeted-therapy in the future.