Researchers with the Francis Crick Institute- and The Institute of Cancer Research recently published research suggesting that a new class of drugs that is helpful in treating breast cancers could help treat some of the hardest-to-treat lung cancers. They published their work in the journal Cell Reports.
The scientists tested drugs that block p110a, which show promise in breast cancer clinical trials, in mice who had lung cancers caused by mutations in the EGFR gene. The RAS gene is mutated in about one in five cancers, resulting in uncontrolled growth.
The team was studying the interaction between the RAS protein and p110a. They found that by blocking the interaction in the mice, the tumors shrank significantly.
“At the moment, patients with EGFR-mutant lung cancers are given targeted treatments that are very effective for the first few years,” stated Julian Downward, team leader. “These drugs are improving, but unfortunately after a couple of years the cancer usually becomes resistant and starts to grow and spread again. The second line of treatment is currently conventional chemotherapy, which is not targeted and has substantial side-effects.”
As a result, Downward proposes that that p110a inhibitors should be investigated as a possible second-line therapy in lung cancers. More preclinical work needs to be done first, but it does appear to be a promising pathway to investigate.
In non-small cell lung cancer (NSCLC), the most frequently mutated oncogenes encode the small GTPase KRAS and the EGFR. The basics of this led to the use of EGFR-targeted tyrosine kinase inhibitors (TKIs) in NSCLC patients with those mutations. A new generation of TKIs have been approved, including AstraZeneca’s Tagrisso (osimertinib). Tagrisso is approved for first-line treatment of metastatic EGFRm NSCLC.
Tagrisso is one of AstraZeneca’s fastest-growing cancer drugs. In the company’s third-quarter financial, sales increased for the quarter by 104 percent to $506 million, and the year-to-date sales at that point were $1.266 billion.
Other TKIs include Novartis’ Imatinib mesylate (Gleevec) and Nilotinib (Tasigna), Bristol-Myers Squibb’s Dasatinib (Sprycel), Pfizer’s Bosutinib (Bosulilf) and Takeda’s Ponatinib (Iclusig).
However, additional resistance has been found in patients receiving TKIs, especially a C797S mutation in EGFR.
In their research, before using the new drugs, tumors took up about two-thirds of the mice’s lungs. When they used drugs to block the interaction between RAS and p110a, the tumors shrank to about one-tenth of the lung space. There were also few side effects.
“As we wanted to pinpoint the specific interaction responsible, we used a genetic technique that would not be practical in a patient treatment,” Downward stated. “We’re looking to develop ways to do this with drugs, as blocking this specific pathway would significantly reduce side-effects, but this work is many years from the clinic.”
He goes on to say, “In the medium-term, investigating existing drugs that inhibit p110a will be the next step. While these have side-effects, including temporary diabetes-like symptoms during treatment, they are still less toxic than chemotherapy.”
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