Validation of therapeutic target ERBB2 in lung cancers
The promise of personalized cancer medicine lies in specific, targeted treatments that attack the unique features driving each patient’s tumor. Funded by Uniting Against Lung Cancer, Dr. Heidi Greulich and her team have identified new cancer-causing mutations in the ERBB2 gene (also called HER2) and potential treatments for patients with tumors harboring these mutations.
In lung cancers, we have identified a number of cancer-causing genes and have approved targeted therapies for two groups of patients, those with tumors driven by EGFR (10-35% of patients) and ALK (3-7% of patients). We know of a number of other cancer-causing genes, including KRAS (15-25% of patients), and are hard at work developing treatments targeting these genes. However, a large number of patients have no targeted therapy option.
All cancers have genetic mutations that disrupt normal functions. As cancers grow, they accumulate more and more mutations, some of which are key drivers of growth but many of which are just passengers. New technology enables geneticists to find all the genes mutated in cancers, but the key to developing new targeted cancer treatments is distinguishing the cancer-causing genes and mutations from the haystack of other genetic anomalies in cancer.
Uniting Against Lung Cancer funded Dr. Heidi Greulich at the Dana-Farber Cancer Institute to accomplish the task of following up on the hundreds of genetic mutations identified in lung cancers and validate whether they are in fact cancer-causing mutations and good drug targets for future clinical trials. In collaboration with UALC Medical Committee members Drs. Kwok-Kin Wong and Matthew Meyerson, Dr. Greulich focused her investigation on mutations to six genes: EPHA3, ERBB2, ERBB4, FGFR4, NTRK2, and NTRK. While the others turned up negative, the team was able to validate new cancer-causing mutations to ERBB2 that are found in lung, breast, ovarian and bladder cancers.
ERBB2 is especially interesting because it is a receptor tyrosine kinase in the same family as EGFR. It sits in the surface of cells and is activated by external signals that tell the cell to grow. While ERBB2 is more commonly associated with breast cancer, Dr. Greulich and her team confirmed mutations to the exterior part of ERBB2 found in lung cancer cells can also drive tumor growth. The team also found that cells with the ERBB2 mutations were sensitive to the inhibitors neratinib and afatinib, new drugs that block both EGFR and ERBB2.
While this research is just one step on the way to developing new personalized treatments, it does support future clinical trials of drugs targeting ERBB2 in lung and other cancers patients who have tumors driven by these mutations.
Greulich et. al. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. PNAS 2012. Published online before print August 20, 2012, doi: 10.1073/pnas.1203201109