Two new studies have identified distinct but complementary strategies to combat resistance to KRAS G12C inhibitors, a critical challenge in treating non-small cell lung cancer. The research, from scientists at Moffitt Cancer Center, details how tumors evade these targeted therapies and offers a preclinical roadmap for developing more durable treatments. One study reveals that cancers can reactivate RAS signaling to escape the effects of KRAS G12C inhibitors, while the second demonstrates that targeting CDK12/13, proteins involved in DNA repair and cell division, can prevent or delay this resistance.
These findings, published in Cancer Research, provide a dual-pronged approach to extend the effectiveness of KRAS-targeted therapies. The RAS gene family produces proteins that act as on/off switches for cell growth. When mutated, as in many cancers, these proteins can become stuck in the “on” position, leading to uncontrolled tumor proliferation. The KRAS G12C mutation is one of the most common and aggressive, found in approximately 10–14% of non-small cell lung cancer cases. While inhibitors targeting this mutation have been a significant advance, their long-term efficacy is often limited by the development of drug resistance. The new research explores how to overcome these resistance mechanisms, offering hope for improved outcomes for patients with this challenging form of lung cancer.
Reactivating a Master Switch
One of the primary ways that tumors develop resistance to KRAS G12C inhibitors is by reactivating the RAS signaling pathway. The initial effectiveness of these drugs comes from their ability to lock the KRAS G12C protein in its inactive, or “off,” state. However, cancer cells can adapt to this pressure by finding alternative ways to turn the RAS pathway back on. This can involve the activation of other RAS proteins, such as wild-type KRAS, NRAS, and HRAS, which are not targeted by the G12C-specific inhibitors. This reactivation of RAS signaling allows the cancer cells to resume their uncontrolled growth, even in the presence of the inhibitor.
The Moffitt researchers found that this adaptive response is a common feature of resistance to KRAS G12C inhibitors. By studying various models of non-small cell lung cancer, they observed that tumors consistently found ways to bypass the drug’s effects by restoring RAS activity. This highlights the need for a more comprehensive approach to RAS inhibition, one that can account for these escape routes. The study demonstrated that a new class of drugs, known as RAS(ON) inhibitors, could effectively shut down these reactivated pathways. Unlike the first-generation inhibitors, which only target the inactive form of KRAS G12C, these next-generation drugs can block both mutant and wild-type RAS proteins when they are in their active state.
A Broader Approach to RAS Inhibition
The development of RAS(ON) inhibitors represents a significant step forward in the quest to overcome resistance. By targeting the active form of RAS, these drugs can prevent the signaling that drives tumor growth, regardless of how the cancer cells have managed to reactivate the pathway. The researchers showed that a RAS(ON) inhibitor called RMC-7977 was able to block these escape routes and restore tumor control in preclinical models. This suggests that a strategy of inhibiting both the “on” and “off” states of RAS could be a powerful way to make KRAS-targeted therapies more durable.
This approach of “vertical pathway inhibition,” where multiple points in a signaling cascade are targeted simultaneously, has shown promise in other types of cancer. For example, in BRAF-mutant melanoma, combining RAF and MEK inhibitors has proven more effective than either drug alone. The new research suggests that a similar strategy could be successful in KRAS-mutant lung cancer. By combining a KRAS G12C(OFF) inhibitor with a RAS(ON) inhibitor, it may be possible to create a more complete and lasting blockade of the RAS pathway, thereby preventing or significantly delaying the emergence of resistance.
Exploiting a New Vulnerability
The second study from the Moffitt team uncovered a different, yet complementary, strategy for overcoming resistance. They found that as cancer cells become resistant to KRAS G12C inhibitors, they also develop a new vulnerability: an increased sensitivity to drugs that target CDK12 and CDK13. These two proteins are cyclin-dependent kinases that play crucial roles in regulating gene expression, DNA repair, and mitosis. The researchers discovered that inhibiting CDK12/13 could selectively kill cancer cells that had become resistant to KRAS G12C inhibitors.
This finding is significant because it suggests that the very process of developing resistance to one drug can make cancer cells susceptible to another. The study showed that CDK12/13 inhibitors disrupt the ability of the resistant cells to repair their DNA and to properly execute cell division. This leads to a state of “mitotic arrest,” where the cells are unable to complete the process of dividing, ultimately leading to their death. This approach offers a way to treat tumors that have already developed resistance to KRAS G12C inhibitors, as well as a potential strategy for preventing resistance from occurring in the first place.
A Combination Strategy for a Complex Problem
The most promising aspect of these two studies is the potential for combining these different approaches to create a more powerful and durable treatment strategy. The researchers explored the effects of co-treating cancer cells with a KRAS G12C inhibitor and a CDK12/13 inhibitor. They found that this combination not only delayed the onset of resistance but could also overcome resistance that was driven by mechanisms independent of RAS signaling, such as the epithelial-mesenchymal transition (EMT). This suggests that a dual-pronged attack on both RAS signaling and the cellular processes that support resistance could be a highly effective approach.
From the Lab to the Clinic
These preclinical findings provide a strong rationale for new clinical trials to test these combination therapies in patients with KRAS G12C–mutant non-small cell lung cancer. By understanding the specific mechanisms that drive resistance, researchers can design more intelligent and effective treatment strategies. The two studies offer a clearer map for how to translate these laboratory findings into clinical practice. The ultimate goal is to extend the durability of KRAS-targeted therapies and to improve outcomes for a patient population that is in great need of better treatment options.
The Future of KRAS-Targeted Therapy
The discovery of KRAS G12C inhibitors was a landmark achievement in cancer therapy, providing the first effective targeted treatment for a mutation that was long considered “undruggable.” However, the emergence of drug resistance has highlighted the need for the next generation of therapies that can overcome this challenge. The research from the Moffitt Cancer Center provides a glimpse into what that future may look like. By developing more sophisticated strategies that anticipate and counter the ways that tumors adapt, it may be possible to turn what is often a temporary response into a long-term and durable remission.
The dual strategies of targeting both the active and inactive forms of RAS, as well as exploiting the new vulnerabilities that arise in resistant cells, represent a significant step forward in this endeavor. These findings underscore the importance of continued research into the fundamental biology of cancer, as it is only through a deep understanding of the enemy that we can hope to defeat it. For patients with KRAS G12C–mutant lung cancer, these new studies offer a reason for optimism, suggesting that more effective and lasting treatments may be on the horizon.
