Scientists have demonstrated the effectiveness of a new drug against a variant of lung cancer that is resistant to therapies effective against other tumors.
The research, divided into two studies, was conducted by a team made up, among others, of Marie-Julie Nokin, of the University of Liège in Belgium, and David Santamaría, of the Cancer Research Center (CIC), an entity joint project of the University of Salamanca and the Superior Council of Scientific Research (CSIC), in Spain.
In recent decades, thanks to greater genomic and molecular knowledge of tumors, new targeted therapies have been designed, which adapt to the specific characteristics of each patient’s tumor more effectively 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 concentrated its efforts on understanding the cellular mechanisms that cause this therapeutic resistance and on tracing new pharmacological possibilities.
KRAS G12C is the oncogenic mutation responsible for a quarter of all cases of lung adenocarcinoma.
The first drugs specifically targeting 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 had access to tumor samples, both before treatment and during the progression of the disease, to compare them.
The authors of the two new studies verified the effectiveness of a targeted therapy, under clinical evaluation, against the KRAS G12C mutation.
Researchers have identified adaptive mechanisms that allow KRAS G12C to reactivate and make it resistant to therapy. “On the one hand, we found evidence indicating that these adaptation mechanisms are relatively frequent and could be the molecular basis of a considerable part of resistant tumors for which the cause has not yet been identified. On the other hand, in the same study we demonstrated that a new drug directed against KRASG12C, currently in the early phase of clinical evaluation, is effective and suppresses tumor progression caused by these adaptive disorders that generate resistance,” explains Santamaría.
Staining of a lung adenocarcinoma with KRAS mutation. (Photo: CIC / CSIC / USAL)
In a parallel study, the scientific team 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 drug resistance have been much less studied.
“We identified that, in the early stages of treatment resistance, BRAF V600E tumors experience 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 Santamaria. “Using animal models, we have shown that drugs that inhibit this enzyme increase oxidative stress to lethal thresholds that prevent tumor progression and significantly slow the evolution of resistant tumors,” he adds.
The difficulty in drug resistance of both mutations, the researcher indicates, is determining the precise and ideal moment in which patients would obtain the maximum 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 was published in the academic journal Nature Communications.
The other is titled “In vivo vulnerability to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFV600E lung adenocarcinoma.” And it was published in the academic journal Cell Reports Medicine. (Source: CIC / CSIC / USAL)
Interview between Time.news Editor and David Santamaría, Expert in Lung Cancer Research
Editor: Welcome, David Santamaría! Thank you for joining us today. Your recent research has shed light on a significant breakthrough concerning lung cancer treatments. Could you start by summarizing the essence of these two studies?
Santamaría: Thank you for having me. Our research focuses on a variant of lung cancer associated with the KRAS G12C mutation. This mutation is responsible for about a quarter of lung adenocarcinomas and presents considerable challenges in treatment, particularly because many patients develop resistance to existing therapies. In our studies, we explored both the mechanisms behind this resistance and the effectiveness of a new drug currently under clinical evaluation.
Editor: That sounds promising. Can you elaborate on what you discovered about the resistance mechanisms?
Santamaría: Certainly. We found that tumors with the KRAS G12C mutation can employ certain adaptive mechanisms to reactivate and continue thriving despite treatment. These adaptations are surprisingly common and could explain why many tumors resisting therapies don’t show identifiable causes. Understanding these mechanisms is crucial for developing more effective treatments.
Editor: Interesting! You mentioned a new drug in your research. What makes this new therapy stand out compared to existing treatments?
Santamaría: This new drug specifically targets the KRAS G12C mutation and has shown effectiveness in suppressing tumor progression related to the adaptive resistance we’ve identified. While other targeted therapies were approved in 2021, our findings suggest that this drug could be a viable option for patients who developed insensitivity to prior treatments. It’s still early in the clinical evaluation phase, but results so far are encouraging.
Editor: That’s fantastic news! For our audience, could you explain how targeted therapies differ from traditional cancer treatments?
Santamaría: Absolutely. Traditional cancer treatments, such as chemotherapy, are often less selective and can harm healthy cells, leading to significant side effects. Targeted therapies, on the other hand, are designed based on the unique genetic and molecular characteristics of a patient’s tumor, which makes them more effective and reduces toxic side effects. Precision medicine allows for a more tailored approach to each patient’s specific cancer.
Editor: How do you envision the future of lung cancer treatment evolving with these advancements?
Santamaría: I believe we are moving towards a future where precision medicine will become the standard of care for lung cancer. Continued research into the genetic profile of tumors, combined with the development of novel therapeutic drugs, will empower clinicians to provide highly effective treatments. Additionally, understanding resistance mechanisms will help us anticipate challenges earlier and potentially combine therapies to prevent or overcome resistance.
Editor: It sounds like a hopeful future is on the horizon. What message do you have for patients currently affected by lung cancer?
Santamaría: I want to emphasize that ongoing research is actively seeking solutions to the challenges posed by lung cancer. If you or a loved one is facing a lung cancer diagnosis, I advise engaging with healthcare professionals who can provide access to the latest treatments and clinical trials. Knowledge is power, and advancements in cancer research hold significant promise for improved outcomes.
Editor: Thank you, David, for your insights and the hopeful developments in lung cancer research. We look forward to hearing more about your work in the future!
Santamaría: Thank you for having me; it was a pleasure to share our findings.