A promising new strategy to treat a common form of lung cancer focuses on a protein whose loss makes it harder for the body to repair damaged DNA, which potentially paves the way for accelerated cell division that can lead to the growth of tumors.
Lung cancer is the leading cause of cancer deaths worldwide. According to the International Agency for Research on Cancer (IARC), the disease was responsible for an estimated 1.8 million deaths in 2020 alone, which the American Cancer Society reports is more than breast, colorectal and prostate cancers combined.
A team of researchers from the Faculty of Biology at the Technion – Israel Institute of Technology in Haifa have been investigating the molecular mechanisms that protect cells from DNA damage, which can be caused by radiation, smoking or other factors.
And because the failure of these protective mechanisms to repair damaged DNA can lead to cancer development, the researchers realized that understanding such mechanisms could be crucial for developing targeted cancer treatments.
“Our DNA is always under attack,” Technion doctoral student Feras Machour, who jointly led the research, tells NoCamels. “We were interested in researching how our cells cope with DNA damage.”
This led to an exploration of how cells deal with DNA damage in order to improve targeted cancer therapies, because numerous forms of cancer have mutations in the proteins or genes that are responsible for maintaining and repairing DNA.
The team focused on the RBM10 protein because it is frequently found to be absent in patients with an aggressive type of lung cancer called lung adenocarcinoma (LUAD), Machour says.
He explains that around 40 percent of all lung cancer patients are affected by this particular form of the disease, and mutations in RBM10, which also make tumors more resistant to current treatments, are found in up to 25 percent of LUAD cases.
This means that a significant number of all lung cancer patients potentially have a mutation of the RBM10 protein.
As such, the researchers set themselves the goal of developing new, personalized strategies to treat the specific type of LUAD that includes a loss of RBM10.
Machour says there has been little previous research into missing or mutated RBM10 in tumors, despite its frequent occurrence in LUAD. He hypothesizes that this is due to the fact that the absence of the protein makes it difficult to create a way to target it.
This led the team to take what Machour calls “a slightly different approach” – looking for genetic signs specific to cells that are missing RBM10, and therefore more susceptible to cancerous growth, in order to remove them.
Analyzing biological data led the team to dozens of “very high scoring” potential genetic identifiers, and they centered on one gene called WEE1 that is already the focus of clinical trials for a molecule that can interact with proteins.
“Our idea was that, since it’s already in stage two clinical trials, maybe we can repurpose the drug for RBM10 deficiency in carcinoma, and then… people with mutations in RBM10 would have a therapeutic option that wasn’t available before,” Machour says.
The team then indeed showed that inhibiting the WEE1 gene is highly effective in eradicating RBM10-deficient lung cancer in mice. The findings were recently published in the Nature journal.
“We were very happy to see that the tumors that had RBM10 mutations were very sensitive to this inhibitor, and the tumor actually shrank significantly in size,” Machour says, “meaning that it might be a very reliable therapeutic option for lung adenocarcinoma patients.”
The potential treatment must now undergo clinical trials in humans, which Machour says requires as yet unsecured collaboration with a major research institute or pharmaceutical company. In all, he says, it could still take up to 15 years for the drug to be on the market.
Machour himself is leaving the Technion for London, where he will continue his post-doctoral studies at the world-renowned Francis Crick Institute, a biomedical research center that is partnered with Cancer Research UK.
Even so, the Technion lab run by Prof. Nabieh Ayoub, who jointly led the research, will continue to work on the RMB10 protein.
“And maybe find combinatorial approaches to make the treatment even more effective,” he says.
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