An approved treatment for BRAF-mutant melanomas may be promising for certain lung cancer patients, according to recent data published in Nature Communications.
The study, “MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated,” shows that lung cancer patients with mutations in the ATM gene are particularly sensitive to Mekinist (trametinib), and use of this MEK inhibitor may be a better and more personalized therapy approach for these patients.
“Normally, lung cancer cells are resistant to MEK inhibition as they activate compensatory signals,” Ferran Fece, one of the study’s two first authors and a former PhD student at the Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, said in a news release. “In contrast, ATM mutant cells fail to do this and subsequently cannot cope with the blocking of MEK and die.”
Lung cancer, the leading cause of cancer-related deaths worldwide, presents a high number of genomic alterations that drive cancer development and progression. Although some of these genetic drivers, like EGFR or ALK mutations, can be targeted with drugs — such as Iressa (gefitinib), Tarceva (erlotinib), and Xalcori (crizotinib) — others, like ATM mutations, are considered “undruggable.”
But these mutations often carry vulnerabilities that can be exploited using drugs that target other proteins — if the proteins that need to be targeted can be identified.
“We knew that cancer mutations can lead to extreme sensitivity to some drugs. But finding these cancer Achilles’ heels is very difficult as they are difficult to predict and extremely rare,” said Michal Smida, the other co-first author. “We screened a large number of gene and drug combinations and got lucky.”
Researchers, using a lung cell line, selectively depleted 10 genes whose loss is usually associated with lung cancer recurrence. Then, each of the obtained cell lines was cultured with 106 anti-cancer drugs (both experimental therapies and those approved by the U.S. Food and Drug Administration).
The two top hits were both in lung cancer cells lacking the ATM gene, which is involved in DNA damage repair. Unexpectedly, one of the inhibitors that most efficiently killed ATM mutant cells was the MEK1/2 inhibitor.
Mekinist was approved by the FDA to treat melanomas with specific BRAF mutations, and clinical trials into MEK inhibitors in other cancers are underway. But their results in lung cancer patients have not been encouraging.
The researchers next proceeded to validade their results, testing different MEK inhibitors in these engineered lung cells, as well as in lung cancer cells with ATM mutations. All test results showed that ATM mutated cells were more sensitive to MEK inhibitors.
The researchers were even able to use ATM mutation status to predict which cells would be sensitive to Mekinist.
Additional tests in mice carrying human lung tumors showed similar results, with the growth of tumors carrying mutations in the ATM gene stopping completely upon administration of the MEK inhibitor selumetinib. In some mice, the researchers even found that the drug induced tumor regression.
Importantly, those effects were more striking than those seen with standard of care therapies, showing that MEK inhibitors may be a promising treatment approach for lung cancer patients carrying ATM mutations.