One of the most exciting and high-impact developments in lung cancer research in the past decade is the observation that lung adenocarcinomas carrying mutations in a gene called EGFR could be targeted with a specific inhibitor of EGFR, resulting in dramatic tumor shrinkage in most such patients. This exciting advance really changed thinking in the field. However, these dramatic responses did not last forever; most responding patients suffered disease recurrence and progression within two years of starting EGFR-directed therapy. Several ways for the tumor to escape and become resistant have been discovered. One of the most interesting is what appears to be a shift in the type of lung cancer, from adenocarcinoma to small cell.

This novel observation, that tumors can escape from effective therapy by shifting to small cell lung cancer, should have important lessons for us about tumor biology. Understanding how this happens should also help us design strategies to prevent this escape.

Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute are leading centers for lung cancer research, with exceptionally large and active clinical programs. Both centers routinely recommend tumor biopsies for molecular analysis, before treatment, and, for patients getting targeted therapy, at the time of disease progression. These paired biopsies from the same tumor in different states (initially sensitive to therapy, then resistant) are a uniquely valuable resource with which to learn about how tumors evolve to become resistant. These two major Centers will come together in this proposal to collect and analyze paired biopsies from our patients with EGFR-mutant adenocarcinoma that became drug-resistant through transformation to small cell.

The shift from adenocarcinoma to small cell may occur because of new mutation(s) in the DNA, or may occur because sets of key regulatory genes were turned on or off. The latter process, changing whether genes are on or off without mutation in the sequence is called epigenetic control of gene expression, and is dependent on the state of methylation of the genes. We will use state-of-the-art DNA sequencing technology and DNA methylation detection technology at Memorial Sloan-Kettering to comprehensively look at both possible mechanisms: genetic or epigenetic.

The high rates of random mutations and gene methylation changes in cancer mean that comparing different types of cancer generally requires analysis of hundreds or even thousands of samples to get a good understanding of the key alterations: There is a lot of background noise. However, using our approach, because we are looking specifically at paired tumor biopsies from the same cancer in different states, we can subtract out most of that background noise, and we should be able to gain useful insights from a very small set of paired samples.

Overall, completion of this relatively straightforward tumor comparison project should have really high impact in at least a couple of ways. First, by focusing narrowly on these genetically linked pairs of tumors of one or the other subtype, we think we will be able to identify key differences that determine whether tumors develop into adenocarcinoma or into small cell lung cancer. Second, again by focusing narrowly on these pairs, we think we will gain significant new insights into how tumors acquire resistance to targeted therapy, a critical issue for many lung cancer patients, and indeed for patients with cancers of all types.