For several decades, RAS has been considered a potent oncogenic driver; however, until the development of KRAS G12C inhibitors, it was deemed “undruggable.”
“This early success with G12C inhibitors, along with additional key insights into targeting RAS, has fueled this explosion and drug discovery, with numerous new RAS inhibitors now in preclinical and clinical development,” said Alice Shaw, MD, PhD, on April 28 during a session at the 2025 American Association for Cancer Research (AACR) Annual Meeting.
The session titled “Unmasking Resistance: Deciphering Mechanisms and Charting New Frontiers in Cancer Therapies,” focused on efforts to overcome resistance and optimize combination therapies for RAS-driven—specifically KRAS-mutant—lung cancer.
Overcoming Resistance to KRAS G12C Inhibitors
While the data are promising, Dr. Shaw, a medical oncologist at Dana-Farber Cancer Institute, Boston, said that overcoming resistance remains a significant challenge.
“As with other targeted therapies in lung cancer, we’re encountering resistance to these RAS inhibitors in the clinic, often within 6 to 12 months,” she said. “This limits their use and their impact.”
Dr. Shaw noted that resistance to KRAS G12C inhibitors is mediated by multiple diverse mechanisms, many of which converge on the RAS/MAPK pathway.
Non-genetic or adaptive mechanisms of resistance can also lead to MAPK reactivation through loss of feedback inhibition of upstream receptor tyrosine kinases (RTKs). Other resistance mechanisms include histologic transformation and transcriptomic changes.
Effective Combination Strategies to Address KRAS Resistance
Dr. Shaw highlighted three combination strategies that have been found to be effective in preventing or delaying resistance. Given the prominent role of the RAS/MAPK reactivation in resistance, there has been a large focus on the development of vertical pathway combinations that target different nodes in the RAS/MAPK pathway.
One of the most successful combinations has been KRAS G12C inhibitors with EGFR antibodies to overcome adaptive reactivation of EGFR in colorectal cancer (CRC). One such example is divarasib in combination with cetuximab.
“The combination of divarasib and cetuximab roughly doubles the response rate compared to divarasib alone and improves progression-free survival (PFS) by about two and a half months,” Dr. Shaw said.
Dr. Shaw said that there are emerging data that also suggest benefits for combining sotorasib with panitumumab (overall response rate [ORR]: 48%) or fulzerasib with cetuximab (ORR: 82%) in KRAS G12C-mutant lung cancer. While the early clinical data are promising, larger studies are needed to determine if the addition of EGFR inhibition to KRAS G12C inhibitors enhances efficacy.
Another vertical strategy, Dr. Shaw noted, involves combining KRAS G12C and SHP2 inhibitors.
“There’s strong rationale for combining KRAS G12C and SHP2 inhibitors, but we’ve been limited in our ability to dose this combination due to toxicity,” she said.
Targeting YAP-TEAD offers another combination opportunity. In preclinical studies, combining KRAS G12C and YAP-TEAD inhibitors has demonstrated the potential for synergistic anti-tumor activity.
“YAP has been reported to activate epithelium mesenchymal transition, which is associated with drug resistance and has been shown to promote the survival of residual drug-tolerant persister cells after targeted therapy,” Dr. Shaw said.
Promising Alternative Approaches to KRAS Resistance
Dr. Shaw highlighted a novel orthogonal combination that targets methylthioadenosine phosphorylase (MTAP)-depleted tumors. MTAP deletions are found in approximately 10% to 15% of patients with lung cancer.
Cancers with MTAP deletions have shown selective vulnerability to PRMT5 inhibition.
In the absence of MTAP, methylthioadenosine (MTA) accumulates, which binds to and partially inhibits PRMT5, making cancer cells more sensitive to further PRMT5 inhibition. Early clinical data assessing MRTX1719, an MTA-cooperative PRMT5 inhibitor, are encouraging.
“Responses were observed in about 20% of patients with various MTAP-deleted cancers and across different dose levels,” Dr. Shaw said. “Among the 26 patients who had MTAP-deleted lung cancer, the response rate was about 30%, and the median duration of response was 7 months.”
KRAS G12C and Immune Checkpoint Inhibitor Combinations
Promising activity has also been observed with the combination of KRAS G12C inhibitors and immune checkpoint inhibitors. In first-line PD-L1-high KRAS G12C-mutant lung cancer, adagrasib plus pembrolizumab yielded a response rate of nearly 60% and a median PFS of almost 28 months.
“This vastly exceeds what we see with pembrolizumab monotherapy in the same setting,” Dr. Shaw said, while acknowledging that toxicities remain a concern.
Moving Beyond Monotherapy for KRAS-Mutant NSCLC
Dr. Shaw called for the need to move beyond monotherapy and emphasized that resistance to KRAS inhibitors will invariably develop when given as single agents. She expressed enthusiasm about orthogonal combinations but also stressed the importance of timing.
“I think it’s important to emphasize that for these orthogonal combinations to have the greatest impact, they need to be used in the frontline setting to deepen initial responses and to limit the emergence of resistance,” she said.
She went on to say this is an exciting time in the field, with many different KRAS inhibitors on the horizon, any of which could transform care for patients with RAS-mutant lung cancer. She encouraged clinical investigators to continue pursuing repeated liquid and tumor biopsies to study resistance.
“I believe that this detailed understanding of resistance will be critical to guiding the next generation of even more effective therapies for RAS cancers,” Dr. Shaw said.
