Editor’s note: We first reported on Dr. Alice Berger’s MERIT Award in April 2021. The story has been updated to include the project’s most recent published findings.
Targeted therapies have transformed outcomes for lung cancer patients. After reduced smoking rates, drugs that take aim at signature alterations in tumor cells are the main reason that the death rate has dropped for people diagnosed with lung cancer. Recently, Fred Hutchinson Cancer Research Center lung cancer researcher Dr. Alice Berger received a National Institutes of Health MERIT Award that will support her efforts to extend these advances to more patients with this cancer.
Inhibitors of a growth- and survival-promoting protein called epidermal growth factor, or EGFR, are one class of targeted therapy that’s helped improve outcomes patients with non-small cell lung cancer. EGFR protein is found in very high amounts in some people’s lung tumors, and the EGFR gene is often mutated such that the protein it encodes is more sensitive to EGFR inhibitors.
“The clinical problem that we're addressing is that not all lung cancer patients have targeted therapy options,” said Berger, who holds the Innovators Network Endowed Chair. “But those existing therapies, such as EGFR inhibitors, only work in specific, genetically defined groups. There’s a fraction of lung cancers — 30% to 40% — that don't have those targetable alterations.”
Berger’s MERIT Award will fund seven years of investigations into RIT1, a gene that’s mutated in a subset of non-small cell lung cancer and other tumors, including some leukemias. Her ultimate goal is to extend the power of targeted therapy to more patients with lung cancer.
In new work published August 9 in Nature Communications, Berger, graduate student Amanda Riley and postdoctoral fellow Dr. Athea Vichas outlined several molecular pathways that RIT1-mutated lung tumors rely on to thrive and which could be potential therapeutic targets.
Berger was inspired to seek out new therapeutic targets for lung cancer by the clinical advances seen for therapies that target other lung cancer-associated mutations. She linked several new genes to lung cancer — including mutated RIT1 — while participating in The Cancer Genome Atlas, a joint program between the National Cancer Institute and the National Human Genome Research Institute to molecularly characterize different cancers on a large scale.
Berger found RIT1 mutations in about 2% of non-small cell lung tumors. This may sound like a small number, but it has a big clinical impact.
“Because lung cancer is so prevalent, [that 2%] amounts to tens of thousands of people,” Berger said.
Two percent of lung cancer cases translates to 13,000 people per year who likely have lung tumors driven by mutations in RIT1. Additionally, another 10 – 14% of lung tumors have extra copies of RIT1, suggesting that it could be involved in cancer initiation, development or progression for even more patients.
When Berger first linked RIT1 to cancer in 2014, very little was known about the gene or the protein it encodes. RIT1 is related to a better-studied protein called Ras, which transmits cellular signals that promote cell growth and survival. Ras is mutated in many types of cancer, including lung cancer. Berger believes that RIT1 may be turning on the same growth- and survival-promoting pathways as Ras through a different molecular strategy.
Currently there are no drugs that target the RIT1 protein, but Berger hypothesized that RIT1 tumors may have vulnerabilities that can be targeted with current drugs or experimental compounds. The team used large-scale screens to identify important genes and molecular sensitivities in RIT1-mutant lung tumors.
“We were trying to identify druggable targets in the most nonbiased way possible, which was going to be through a broad screening approach,” Riley said.
By combining CRISPR-based gene editing and small molecule inhibitor screens, the team discovered more about the cellular processes in which RIT1 plays a role, as well as identify a molecular pathway that appears to work in concert with mutant RIT1 to promote lung tumor development, growth and survival.
Berger’s MERIT Award will allow her to build on her most recent findings and further explore how these pathways intersect with altered RIT1 to cause cancer, as well as strategies to target them to potentially kill off RIT1-mutated cancer cells.
When her team began the project, almost nothing was known about how RIT1 functions in cells.
“This is one of the first genome-wide explorations into what RIT1 is doing,” Berger said.
The researchers found that, surprisingly, mutating the RIT1 gene alone may not do much to drive cancer. But in a preclinical model of lung cancer, the team showed that when mutated RIT1 occurs alongside a mutated gene that encodes protein called Yap (which also didn’t promote cancer by itself), the two mutants work together to cause cancer.
“We think potentially that Yap activation may need to co-occur with RIT1 to drive tumorigenesis [cancer development]. That's the hypothesis that we want to explore,” Berger said. “If that's true, then inhibiting Yap might be a good therapeutic strategy [for RIT1-mutant lung tumors].”
Riley, Vichas and Berger were also surprised when their screens linked RIT1 to a critical cellular process: cell division. Normal cells use many checks and balances to make sure that each daughter cell gets the right number of chromosomes. Tumor cells often jettison these safeguards to keep dividing.
One important cell-division precaution is the spindle assembly checkpoint, during which cells make sure that the molecular machinery needed to properly separate chromosomes is in place — and will activate an emergency brake if it’s not.
After seeing that many genes involved in the spindle assembly checkpoint were essential to the survival of RIT1-mutant cells, and these cells were also sensitive to inhibitors that blocked key enzymes in this process, “We started exploring this idea that RIT1 itself is weakening the spindle assembly checkpoint,” Riley said.
She found that mutated RIT1 allows cells to rush through the spindle assembly checkpoint. Though this this scramble toward cell division could help speed up tumor growth, it could also mean that drugs or compounds that block some aspect of this checkpoint could more easily trip up RIT1-mutant cells.
Indeed, Riley saw that RIT1-mutant cells are much more sensitive than normal cells to compounds that target a key component of the spindle assembly checkpoint. Berger plans to exploring this sensitivity to possibly lay the groundwork for a clinical trial testing an experimental drug that blocks this enzyme in RIT1-mutated lung cancer.
Riley will investigate a particular aspect of the spindle assembly checkpoint, a molecule that may be working to control levels of RIT1 protein. Excess RIT1 protein appears to a consistent result of RIT1 mutations or amplifications, and Berger’s team will also study the cellular ramifications of too much RIT1.
If too much RIT1 is itself a problem, it could mean that the potential therapeutic targets that Berger’s team has found in RIT1-mutant tumors could also be targets in tumors with extra copies of the RIT1 gene — a line of investigation that Berger is eager to follow up on.
She also noted that the findings could extend beyond lung cancer. RIT1 gene changes are seen in other tumors, including some uterine, endometrial and bladder cancers, which raises the possibility that the therapeutic strategies that Berger’s team identifies could be applied to more patients. And their screening strategies could be used by researchers working to identify other rare cancer-driving mutations, she said.
Fred Hutch’s ties to Seattle Cancer Care Alliance and its deep scientific resources have been central to the success of her group’s work, Berger said. This includes studying the only preclinical animal model of RIT1-driven tumors with the help of the Hutch Preclinical Modeling shared resource. These special mice will allow Berger and her team to study how RIT1 promotes tumor development and intersects with other molecular pathways, as well as test potential drugs to target these tumors.
“We also interact a lot with [Hutch and SCCA lung cancer specialist] Christina Baik and the lung cancer medical oncologists, which helps us to remain focused on our ultimate goal of improving survival and outcomes for patients with lung cancer,” she said.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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