New Research Offers Hope for KRAS-Driven Lung Cancer

Lung cancer remains one of the most challenging cancers to treat, particularly when it is driven by mutations in a gene called KRAS.  

At this year’s American Association for Cancer Research Annual Meeting, Moffitt Cancer Center experts presented new research exploring a promising strategy to improve treatment outcomes for these hard-to-treat cancers by blocking how cancer cells survive therapy-induced stress. 

KRAS mutations are found in about 25% to 30% of non-small cell lung cancers, the most common type of lung cancer. These mutations help cancer cells grow and divide uncontrollably. While recent advances have led to the development of drugs that directly target certain KRAS mutations, such as KRAS G12C inhibitors, patients often experience a limited window of benefit. 

“After initial response of KRAS G12C targeted therapies, resistance arises often within four to six months,” Simon Bayle, PhD, lead author on the study explained. “Studies have identified several different mechanisms of acquired resistance, including additional KRAS mutations, activation of bypass pathways.” 

Stopping Resistance  

The new study focuses on a cellular process called autophagy, which is essentially a recycling system inside cells. Under stress, such as starvation or cancer treatment, cells can break down and reuse their own components to generate energy and survive. 

“Autophagy is a mechanism where cells under nutrient stress recycle material to maintain survival,” Bayle said. “It has been shown to help cancers resist treatment.” 

A key regulator of this process is ULK1, which acts as an “on switch” for autophagy. The researchers hypothesized that blocking ULK1 could shut down this survival pathway and make cancer cells more sensitive to treatment. 

To test this, the team developed a new ULK1 inhibitor called MR-2088. In KRAS-mutant lung cancer models, MR-2088 blocked autophagy and impaired tumor cell survival, especially when combined with KRAS pathway inhibitors. 

“The synergy of MR-2088 and KRAS inhibitors is highly significant,” Bayle said. “We observed reduced tumor growth, improved survival and delayed regrowth and resistance. We are optimistic this will translate to human trials.” 

Reducing Relapse  

To understand why tumors return after treatment, researchers used DNA barcoding and gene expression profiling. Rather than finding new genetic mutations driving resistance, they observed that cancer cells shift into a reversible, drug-tolerant state. 

“What we realize now is that cancer cells use epigenetic and transcriptional programs to survive therapy,” Bayle explained. “The goal is to identify and target these adaptive resistance mechanisms.” 

These “drug-tolerant persister” cells can enter a dormant state during treatment and later regenerate the tumor. 

The findings suggest that combining KRAS inhibitors with autophagy blockade may help eliminate these persistent cells and reduce relapse. 

“Once we understand which patients are most likely to respond, we anticipate that combining KRAS G12C and ULK1 inhibitors will improve overall survival,” Bayle said. 

Researchers note that autophagy is also important for normal cell function, so safety remains a consideration. However, more selective ULK1-targeting approaches are being explored. 

While further research is needed before clinical use, the study points to a promising strategy: not only blocking cancer growth signals, but also disrupting the survival systems that allow tumors to withstand treatment.