New research from Vanderbilt investigators suggests that clinicians should take a deeper dive into distinguishing EGFR mutations when prescribing targeted therapies for non-small-cell lung cancers.
EGFR exon 19 deletion mutations are the most common EGFR mutations in patients with lung cancer. However, the term “exon 19 deletion” is a catch-all phrase used to denote more than 20 distinct EGFR mutations that have different genomic coordinates and different protein structures. Despite these differences, all EGFR exon 19 deletion mutations are currently treated the same in the clinic.
The team’s goal was to provide data that would support bringing further precision into the care of patients with EGFR-mutant lung cancer. Coupling computational, biophysical and biochemical methods with patient level data, the researchers showed that allele-specific differences matter with respect to how individual exon 19 deletion variants respond to EGFR-directed tyrosine kinase inhibitor targeted therapies. Meaning, even within the “bin” of EGFR exon 19 deletion mutations, there are some mutations within this bin that are more or less sensitive to currently available EGFR targeted therapies used in the clinic. Through their analyses, the researchers provide a framework for how to better classify the heterogenous group of EGFR exon 19 deletion variants and offer suggestions for which EGFR-directed therapies may be most efficacious in each group.
The work, published in Proceedings of the National Academy of Sciences, is the latest finding from an interdisciplinary team from the Vanderbilt University lab of Jens Meiler, PhD, professor of Chemistry, Pharmacology and Biomedical Informatics, and the Vanderbilt University Medical Center lab of Christine Lovly, MD, PhD, Ingram Associate Professor of Cancer Research and associate professor of Medicine. Adam Smith, PhD, associate professor of Chemistry from the University of Akron, is also a key member of the team, providing his expertise in biophysics and membrane-bound proteins.
Benjamin Brown, PhD, the study’s lead author and a co-corresponding author, did part of his graduate work mapping out the effects of these genomic alterations on protein structures. Brown said that he and colleagues have created an interdisciplinary pipeline utilizing the different skill sets from the three labs.
“I am not actually a cancer biologist,” Brown said. ”I am more in the realm of computational chemistry and computational structural biology. Engaging with friends and colleagues in other scientific disciplines creates a real opportunity for synergism.”
The team has previously revealed the value of scrutinizing the original activating mutation when a tumor develops resistance to a targeted therapy instead of focusing solely on the acquisition of new mutations within that tumor. They characterize their research approach “Personalized Structural Biology” because they investigate beyond tumor genomics and delve into the atomic structures of key proteins and allele placements on chromosomes.
“Our cross-disciplinary team’s goal is to provide evidence to bring more precision and more personalization to the care of patients with cancer by tacking a ‘deeper dive’ into the DNA and resultant protein level changes within the tumor,” said Lovly, a corresponding author on the study.
The research received support from the National Cancer Institute, the National Institute of General Medical Sciences, LUNGevity Foundation, the Phran Galante Research Fund, the National Institutes of Health, the National Science Foundation and a Ruth L. Kirschstein NRSA fellowship.
Brown contributed equally on the paper and research with Yun-Kai Zhang, PhD, of Vanderbilt and Soyeon Kim, PhD, of the University of Akron. Other Vanderbilt authors include Yingjun Yan, Zhenfang Du, PhD, Michele LeNoue-Newton, PhD, and Meiler.