While our bodies can have a wide range of naturally occurring, harmless mutations in different genes, some mutations, called driver mutations, are key to driving the development of cancer. There are many driver mutations. Researchers have been developing drugs that target specific driver mutations in lung cancer, creating therapies for those patients whose lung cancer harbors them.
Early Targeting of EGFR
In the early 2000s, EGFR was the first gene in non-small cell lung cancer (NSCLC) to be matched with a targeted therapy. Originally, researchers focused on the two driver mutations in the EGFR exons, sections of the EGFR which contain the code for the EGFR protein. These driver mutations (exon19 deletions and exon21 L858R substitution mutations) are present in approximately 67% of patients with EGFR-positive NSCLC, or NSCLC tumors that test positive for specific EGFR mutations. Other EGFR driver mutations were also known to be scattered throughout exons 18-21, but these driver mutations were less common and were not successfully paired with a targeted therapy.
Early targeted therapies for tumors with the exon19 and exon21 L858R EGFR driver mutations included erlotinib, gefitinib, and afatinib. They are part of a class of drugs known as tyrosine kinase inhibitors, or TKIs, which bind to a specific part of the EGFR protein to inhibit its activity.
“These treatments were very important because they opened the door to a new world of personalized medicine,” says John Heymach, MD, PhD, professor and chair of the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center and member of LUNGevity’s Scientific Advisory Board.
Unfortunately, the cancer would inevitably develop drug resistance and progress. Researchers identified the most common cause of this drug resistance and developed osimertinib, a third-line treatment originally intended to be given to patients once their tumors became resistant to other treatments. However, osimertinib was so well tolerated and effective that it became the gold standard for the first-line treatment of patients with metastatic NSCLC and exon19 and exon 21 L858R EGFR mutations.
Despite this progress in the field, patients whose tumors had other EGFR driver mutations still didn’t have any targeted therapy options. Without a specific therapy for exon20 insertion driver mutations, found in approximately 9% of patients with EGFR+ NSCLC, doctors would often have to choose between keeping their patients on chemotherapy or trying a drug like osimertinib and hope that it was effective for patients with any EGFR mutation.
Dr. Heymach and his team of researchers were convinced that there was a better way to treat patients with EGFR exon20 driver mutations. As described in their research papers published in Nature Medicine (2018) and Cancer Cell (2022), the team engineered cell lines to mimic the different exon20 driver mutations seen in patients. Using these cells lines, they screened every known TKI drug and all the failed drugs that were not effective enough to make it through clinical testing.
“The idea was that maybe, in the past, the researchers had tested the drug on patients with the exon 19 and exon L858R EGFR mutations and it failed, but maybe if the researchers tested the drug on patients with exon20 driver mutations, the treatment might have worked,” explains Dr. Heymach.
Their hypothesis turned out to be true. One failed drug, poziotinib, a small molecule TKI, showed promising results – first in the EGFR exon20-mutated cell lines and later in patients with EGFR exon20 driver mutations. This drug is currently under review with the Food and Drug Administration (FDA) for treating NSCLC with HER2 exon20 driver mutations and is poised to be considered for patients with EGFR exon20 driver mutations as well.
Drilling Deeper into EGFR Exon20
Groundbreaking results from Dr. Heymach’s lab, published in a 2021 Nature paper, suggest a new way to think about EGFR driver mutations, and this research suggests poziotinib may work best in specific subtypes of EGFR exon20 mutations.
“Until now, we’d classified driver mutations based on where the mutations are in the DNA. But this new research uses computational modeling to visualize where the mutations are in 3-D. It’s kind of like we’ve been looking for errors in the 2-D blueprint of a house. Once you can see the completed house in 3-D, the error – such as a tiny garage that won’t fit a car – becomes really obvious.”Dr. John Heymach
In the case of exon20 driver mutations, the mutations caused changes to a binding pocket where the classical EGFR drugs would bind. “The altered structure explained why the classical EGFR drugs wouldn’t work against EGFR exon20 mutations,’ explains Dr. Heymach. “The EGFR exon20 mutations caused the binding pocket to be too small. The drugs couldn’t fit.”
By providing specific biochemical data on the size and shape that would be optimal for binding to this pocket, Dr. Heymach and his collaborators have laid the groundwork for pharmaceutical companies to quickly develop targeted therapies that are likely to bind to the mutated EGFR protein and inhibit cancer growth in patients with EGFR exon20 driver mutations.
Making Personalized Medicine Even More Personal
Expanding this 3-D analysis allowed the researchers to look at the structural changes caused by more than 100 atypical EGFR driver mutations. This allowed the researchers to visualize each mutation on the 3-D model and classify the mutations by their overall effect on the protein shape and structure.
“We identified four distinct subtypes of EGFR mutations, and we have identified the existing therapies that are most likely to be effective (and ineffective) at treating each subtype,” says Dr. Heymach. “It’s not feasible to conduct 100 clinical trials on 100 EGFR mutations, but it is very feasible to conduct clinical trials on four subtypes of EGFR mutations.”
Currently, several drugs have shown promising results in clinical trials for patients with metastatic NSCLC harboring EGFR exon20 mutations. While that testing is likely to continue, it is also probable that researchers will start considering these four subtypes of EGFR mutations as they develop future targeted therapies.
Past Investments in Research Yield an Exciting Future
The recent advances in understanding EGFR exon20 mutations have opened many avenues of exciting research. There is a lot of work being conducted to understand the mechanisms of resistance that cause tumor cells to begin to grow again after being treated with targeted therapies. Researchers are also studying other treatment approaches for patients with EGFR exon20 driver mutations, such as combining treatment options, developing smaller inhibitors that can fit inside the smaller binding pocket, and exploring cutting-edge immunotherapy options.
The results from Dr. Heymach and his team are also inspiring other researchers to model the 3-D structural changes that are caused by other driver mutations to help guide us toward optimizing treatment for patients.
These tremendous advances in in our approach to treating lung cancer patients build upon previous advances in the field. The progress we see in lung cancer treatment relies on financial support and professional mentorship to build a robust pipeline of researchers who commit their careers to improving outcomes for lung cancer patients.
LUNGevity Foundation is proud to have offered such support to Dr. Heymach in 2007 and again in 2011. Using these opportunities as a springboard, Dr. Heymach established a top-notch lung cancer research laboratory with a stellar reputation for mentoring scientists interested in careers in lung cancer.
“The financial and professional support of LUNGevity’s research awards has been very impactful in my career, particularly when I was starting out as a junior faculty member,” notes Dr. Heymach. “These research awards are critical seed grants that help researchers conduct preliminary work. Strong preliminary research gives them a big advantage when competing for national research grants.”
“By supporting research, participating in clinical trials, and educating ourselves – the lung cancer community as a whole is making tremendous strides toward a world where we can find lung cancer, treat it, and live.”
Dr. Heymach previously sat down for a Q&A on targeted therapy options for patients with EGFR Exon20+ NSCLC.