A recent study led by Dr. Ravi Salgia and his team of researchers from City of Hope has identified nongenetic mechanisms that play a crucial role in lung cancer patients developing resistance to a commonly used cancer treatment. The findings of the study were published in the journal Science Advances on October 13.
The study focused on resistance to the anti-cancer drug sotorasib in patients with non-small cell lung cancer (NSCLC). Sotorasib is designed to inhibit a specific mutation of the protein KRAS G12C, which causes uncontrolled cell growth.
The researchers discovered that while most tumor cells initially respond to sotorasib, some cells can become tolerant to the treatment without undergoing genetic mutations or alterations. Instead, these cells manipulate the KRAS-sotorasib interaction network, leading to resistance. Interestingly, when sotorasib treatment is discontinued, the tumor cells become sensitive to the drug again, indicating that the resistance is reversible and driven by nongenetic mechanisms.
However, if the treatment continues for an extended period, genetic mutations can occur, resulting in permanent resistance to the medication.
Furthermore, the study revealed that NSCLC cells with pre-existing genetic mutations that make them resistant to sotorasib can still respond to the drug when used in combination with another FDA-approved anti-cancer therapy called carfilzomib. This combination treatment acts synergistically and employs nongenetic mechanisms.
KRAS mutations are present in various types of cancer, including approximately 30% of NSCLC patients. Small molecule inhibitors that target the mutated KRAS protein, such as sotorasib, have been shown to be effective initially beyond first-line settings. However, over time, tumors develop resistance to the medication. This resistance can either be present from the start or acquired during therapy. Traditionally, it has been believed that genetic mutations are the primary drivers of this resistance. However, this study suggests that nongenetic mechanisms also play a significant role.
These findings not only demonstrate the complex interplay between genetic and nongenetic mechanisms in cancer treatment resistance but also offer a potential therapeutic opportunity for NSCLC patients. Importantly, the study highlights the impact of the flexibility of the KRAS molecule on treatment response, which had not been previously appreciated. For example, resistance to sotorasib does not necessarily mean resistance to other KRAS inhibitors like adagrasib, indicating that changes induced by sotorasib may not hinder KRAS interaction with alternative treatments.
The study also suggests alternative treatment strategies, such as the combination of carfilzomib and sotorasib, for managing challenging and refractory NSCLC KRAS G12C tumors. This emphasizes the need to determine the type of resistance a patient has to personalize their treatment. Based on these promising results, the research team is planning to initiate a clinical trial at City of Hope.
In conclusion, this study sheds light on the importance of nongenetic mechanisms in lung cancer treatment resistance and provides potential avenues for overcoming this resistance in NSCLC patients.
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- Source: Coherent Market Insights, Public sources, Desk research
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