Nongenetic mechanisms of resistance to cancer therapy discovered, offering new hope for lung cancer patients

In a recent research study led by Dr. Ravi Salgia, a renowned expert in medical oncology, a team of scientists from City of Hope, a prominent cancer research and treatment institution in the United States, along with collaborators from other organizations, have uncovered vital insights into the development of resistance in lung cancer patients undergoing a specific cancer therapy. Their significant findings were published in the October 13 issue of the journal Science Advances.

The research delved into the resistance observed in patients with non-small cell lung cancer (NSCLC) receiving the anti-cancer drug sotorasib. Sotorasib targets a specific mutation of the KRAS G12C protein, known to promote uncontrolled cell growth.

The study’s outcomes indicate that initially, most tumor cells respond to sotorasib treatment. However, some cells can develop resistance to the therapy through nongenetic mechanisms that affect the interaction between KRAS and sotorasib. Importantly, it was discovered that withholding sotorasib treatment could lead to the re-sensitization of tumor cells, implying that this resistance is reversible and primarily governed by non-genetic factors.

Nevertheless, with prolonged treatment, there’s a risk of genetic mutations emerging, which can result in permanent resistance to the medication.

Furthermore, Dr. Salgia and the team found that patients with NSCLC cells already possessing genetic mutations that make them resistant to sotorasib could benefit from a combination of sotorasib and carfilzomib, an FDA-approved anti-cancer therapy used for other cancer types. The synergy between these two treatments involves nongenetic mechanisms.

KRAS mutations are prevalent in various cancer types, including around 30% of NSCLC patients. While drugs like sotorasib, which specifically target the mutated KRAS protein (G12C), are initially effective, their efficacy diminishes over time, indicating the development of medication resistance. This resistance can be inherent, meaning it exists before treatment due to pre-existing mutations, or acquired, induced by therapy. Traditionally, it was believed that these resistance mechanisms were primarily genetic. However, thanks to the work of Dr. Salgia and his team, it is now increasingly clear that non-genetic factors play a crucial role in therapeutic resistance.

This study not only underscores the interplay between genetic and non-genetic factors in cancer treatment resistance but also offers a promising avenue for addressing resistance in NSCLC patients. What’s particularly remarkable is that resistance to sotorasib doesn’t necessarily equate to resistance to other KRAS inhibitors like adagrasib, highlighting the potential flexibility of the KRAS molecule in treatment responses. The findings by Dr. Salgia and his team point to alternative treatment strategies, such as the combination of carfilzomib and sotorasib, for managing challenging and refractory NSCLC KRAS G12C tumors. This underscores the importance of determining the type of resistance a patient has to tailor their treatment accordingly. Building on these exciting preclinical results, the research team is actively preparing to launch a clinical trial at City of Hope.

Source: City of Hope National Medical Center

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