Studies identify complementary approaches to overcome drug resistance in KRAS G12C–mutant lung cancer

Two companion studies published in Cancer Research from scientists at Moffitt Cancer Center identify distinct but complementary approaches to overcoming drug resistance in KRAS G12C–mutant non-small cell lung cancer. 

RAS genes produce proteins that act like on/off switches for cell growth. In healthy cells, this helps regulate normal tissue function. But when RAS is mutated, especially in cancers like non-small cell lung cancer, it can become stuck in the "on" position, driving uncontrolled tumor growth. KRAS G12C is one of the most common and aggressive mutations. According to the Lung Cancer Foundation of America, approximately 15–25% of patients with non-small cell lung cancer have a KRAS mutation, with the G12C subtype being the most common, found in about 10–14% of cases. 

The first study shows that cancers can reactivate RAS signaling to evade KRAS G12C inhibitors, but next-generation RAS(ON) inhibitors can block this escape and restore tumor control. The second study demonstrates that targeting CDK12/13, key regulators of DNA repair and mitosis, can delay or prevent resistance and selectively kill resistant cancer cells. Together, these findings offer a dual-pronged strategy to extend treatment response and improve outcomes for patients. 

Key findings: 

• Tumors treated with KRAS G12C inhibitors often reactivate RAS signaling through multiple resistance mechanisms. 

• RAS(ON) inhibitors including RMC-7977 can block both mutant and wildtype RAS, shutting down these escape routes. 

• Resistance is also accompanied by increased sensitivity to CDK12/13 inhibitors, which disrupt DNA repair and induce mitotic arrest.KRAS and CDK12/13 inhibitor co-treatment delayed resistance and could overcome RAS-independent, EMT-driven resistance mechanism 

• These studies offer a preclinical roadmap for new clinical trials aimed at extending the durability of KRAS-targeted therapy. 

Why is resistance to KRAS G12C inhibitors such a critical challenge? 
These therapies have been game changers, but their benefits often don't last. Tumors find ways to reactivate growth pathways or adapt through non-genetic mechanisms, making resistance common. 

How do RAS(ON) inhibitors help address this? 
RAS(ON) inhibitors target the active state of RAS, which allows researchers to shut down not just the original driver mutation but also the wildtype RAS that tumors often turn to as a workaround. This helps close off escape routes. 

Where does CDK12/13 inhibition fit in? 
Resistance also makes tumors vulnerable in another way. They become more dependent on DNA repair and mitotic control. CDK12/13 inhibitors exploit this weakness, inducing mitotic arrest and tumor cell death in resistant models 

What happens when you combine these approaches? 
Combining KRAS G12C inhibitors with CDK12/13 blockade delayed or prevented the emergence of resistance in both cell culture and animal models, extending the duration of treatment response. 

How could these findings impact patients? 
These two studies provide a clearer map for translation into the clinic. By focusing on understanding the precise mechanisms of resistance, combinations of agents can be appropriately delivered to overcome the resistant state. 

These studies were supported by the National Cancer Institute (5R01CA262530-0, P30-CA076292) and State of Florida Bankhead Coley Grant (5BC07).