When a tumor mutates and develops resistance to a targeted therapy, researchers often focus on the acquisition of new mutations within the drug target as they seek an alternative treatment, but a team of Vanderbilt scientists has shown this may not be sufficient.
Instead, they gave renewed scrutiny to the original activating mutation present before initiation of the targeted therapy and the role that this original activating mutation plays in the development of drug resistance. This line of inquiry yielded results that can be quickly translated to the clinic.
The study, published in Clinical Cancer Research, provides clinicians genomic guidance for surveillance of targeted therapy resistance in patients with EGFR-mutant non-small cell lung cancer — and more importantly — another drug option when resistance occurs.
“We’ve been thinking about therapeutic resistance in a drug-centric manner,” said Christine Lovly, MD, PhD, associate professor of Medicine in the Division of Hematology and Oncology and the study’s senior author.
“However, our work shows that it is not enough to think about the drug alone; you have to think about the drug and the tumor. What’s the original mutation in the tumor and how does that interplay with the drug to then come up with the mechanism of drug resistance?”
The lead authors of the study, Benjamin Brown, and Yun-Kai Zhang, PhD, did predictive modeling of the resistance mutation, EGFR G724S, in combination with the two most common drug activating mutations, EGFR Ex19Del and EGFR L858R, with in vitro drug-response models and patient genomic profiling. They sought to understand how resistance developed to osimertinib, a targeted therapy that received U.S. Food and Drug Administration (FDA) approval in 2017.
They determined that resistance to osimertinib occurred differentially between EGFR Ex19Del and EGFR L858R. Their predictive modeling also revealed that afatinib, another targeted therapy approved by the FDA in 2013, was effective against the G724S resistance mutation.
“As these drugs are being developed, we always want to push the best drugs that are most potent and have the best effects everywhere in the body,” Lovly said.
“If we can say when resistance develops to the best drug, ‘Guess what? We already have an FDA-approved other option,’ that’s wonderful because we don’t have to spend 10 more years to develop an alternative drug.”
The study was a joint project between her lab and the lab of Jens Meiler, PhD, professor of Chemistry. It has scientific implications as well as clinical implications.
“Our study brings out the new idea that we cannot only focus on the resistance mutation,” Zhang said.
The researchers did a detailed analysis of specific Ex19Del mutant variants that can co-occur with the resistance mutation G724S. Brown noted that these variants could increase or decrease the probability of developing resistance to osimertinib.
“Understanding these differences allows us to profile patients and give them the best treatment possible, which is super cool, especially when you are somebody who sits in front of a computer all day looking at little atoms move around,” Brown said. “It’s very gratifying to have an effect on people.”
A teamwork approach is absolutely essential for helping cancer patients whose cancers relapse or become resistant to treatment, Lovly said.
“It’s not enough to just say this tumor stopped responding,” she said. “We need to know why it stopped responding to the therapy in order to make the next best therapy . . . The beautiful thing about being at a big academic center like Vanderbilt is we have all these experts. If we work together, we are going to make better treatment outcomes for our patients.”
Meiler is a member of the Vanderbilt University Program in Personalized Structural Biology.
“I am excited to observe how our program in Personalized Structural Biology in collaboration with the Cancer Center begins to improve treatment of patients in tangible and measurable ways,” Meiler said.
“This success is possible because of the intimate integration of basic and applied research at Vanderbilt University and Medical Center.”
Other authors of the study from Vanderbilt include David Westover, PhD, Yingjun Yan, MS, Huan Qiao, MD, PhD, Vincent Huang, Zhenfang Du, PhD and Jarrod Smith, PhD.
