New drug against a resistant variant of lung cancer

Scientists have demonstrated the effectiveness of a new drug against a variant of lung cancer which is resistant to therapies that are effective against other cancers.

The research, carried out in two studies, has been carried out by a team made up of, among others, Marie-Julie Nokin, from the University of Liège in Belgium, and David Santamaría, from the Cancer Research Center (CIC), a joint entity from the University of Salamanca and the Higher Council for Scientific Research (CSIC), in Spain.

In recent decades, thanks to greater genomic and molecular knowledge of cancer, new targeted therapies have been designed, which adapt to the specific characteristics of each patient’s tumor in a more effective way and with less exposure to toxic side effects. However, although these therapies, also known as precision medicine, have demonstrated their potential, some tumors end up developing insensitivity to the treatment. This is why the scientific community has focused its efforts on understanding the cellular mechanisms that cause this therapeutic resistance and on tracking new pharmacological possibilities.

KRAS G12C is the oncogenic mutation responsible for a quarter of all lung adenocarcinoma cases.

The first specific drugs against the KRAS G12C mutation were approved for clinical use in 2021 and, since then, various studies have described tumor alterations that could explain resistance to them in 50% of patients. David Santamaría’s team accessed tumor samples, both before treatment and during the progress of the disease, to compare them.

The authors of the two new studies have verified the effectiveness of a targeted therapy, in the process of clinical evaluation, against the KRAS G12C mutation.

The researchers identified adaptive mechanisms that allow the reactivation of KRAS G12C and make it resistant to therapy. “On the one hand, we have found evidence that indicates that these adaptive mechanisms are relatively frequent and could be the molecular basis of a considerable part of resistant tumors with no cause identified to date. On the other hand, we have shown in the same study that a new drug directed against KRASG12C, currently in the early process of clinical evaluation, is effective and suppresses tumor progression caused by these adaptive disorders that generate resistance,” explains Santamaría.

Staining of a KRAS mutated lung adenocarcinoma. (Photo: CIC / CSIC / USAL)

In a parallel study, the scientific team has also investigated the mechanisms that induce resistance to drugs directed against BRAF V600E, a genetic mutation that causes 4% of lung adenocarcinomas and whose mechanisms of resistance to medication have been much less studied.

“We have identified that, in the initial stages of resistance to treatment, BRAF V600E tumors suffer high oxidative stress that prevents tumor progression, but the activity of an enzyme alleviates this oxidation, allowing tumor survival and eventual development. of pharmacological resistance,” explains Santamaría. “Using animal models, we have proven that drugs that inhibit this enzyme raise oxidative stress to lethal thresholds that prevent tumor progression and greatly slow the evolution of resistant tumors,” he adds.

The difficulty in drug resistance of both mutations, indicates the researcher, lies in determining the precise and ideal moment in which patients would obtain the greatest benefit by implementing a change in treatment. Studies currently underway are focused on finding biomarkers that can guide clinical oncologists in the future.

One of the studies is titled “RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade.” And it has been published in the academic journal Nature Communications.

The other is titled “In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFV600E lung adenocarcinoma.” And it has been published in the academic journal Cell Reports Medicine. (Source: CIC / CSIC / USAL)