Targeting metabolic pathways could prevent relapse in KRAS-mutant cancers

Our cells rely on tightly regulated signaling pathways to control when they grow, divide, and survive. When these regulatory systems are disrupted, cells can acquire the ability to grow uncontrollably and become cancerous. One of the most important cancer-related signaling molecules is the Kirsten rat sarcoma viral oncogene homologue (KRAS), which functions like an on/off switch for cell growth. Normally, KRAS is activated only when growth signals are needed. However, mutations in the KRAS gene can keep the KRAS protein locked in an active state, causing continuous cell growth and division. KRAS mutations are among the most common drivers of cancer, particularly lung, pancreatic, and colorectal cancers.

Although KRAS has been recognized as a major cancer driver for decades, developing drugs to target it has been highly challenging. Sotorasib became the first approved KRAS inhibitor in 2021 to treat certain forms of non-small cell lung cancer (NSCLC). It works by locking specific mutated KRAS proteins in an inactive state, thereby slowing tumor growth and opening new therapeutic opportunities for patients with KRAS-mutant cancers. However, KRAS inhibitor treatment often leaves behind a small population of resilient cancer cells called drug-tolerant persister cells (DTPs), which survive treatment and may later contribute to cancer relapse.

Now, researchers from Chiba University, Japan, have discovered that DTPs are not simply inactive cells that passively survive KRAS inhibition. Instead, they undergo extensive biological changes and become dependent on metabolic pathways that help them adapt and survive. Their findings, published in the journal Communications Biology on May 26, 2026, suggest that these adaptations may also expose new vulnerabilities that could be therapeutically targeted.

The study was led by Associate Professor Shigeki Aoki, together with Mr. Hiroki Furukawa and Professor Kousei Ito from the Graduate School of Pharmaceutical Sciences at Chiba University, Japan, in collaboration with Dr. Keitaro Umezawa from the Tokyo Metropolitan Institute for Geriatrics and Gerontology, and Dr. Yuchen Sun from the National Institute of Health Sciences, Japan.

"The central message of our study is that the same adaptive process that allows cancer cells to survive KRAS-targeted therapy may also expose a new weakness. Targeting this weakness could provide a strategy to eliminate residual KRAS-mutant cancer cells after KRAS inhibition, prevent relapse at its source, and ultimately move KRAS-targeted therapy closer to curative treatment," says Dr. Aoki.

To investigate how DTPs survive treatment, the researchers exposed laboratory models of KRAS-mutant NSCLC and pancreatic ductal adenocarcinoma (PDAC) to KRAS inhibitors, allowing the cells to enter a reversible drug-tolerant state resembling DTPs. The team then analyzed how the DTPs adapted over time.

The researchers observed that DTPs temporarily stopped proliferating and adopted features resembling cellular senescence, a state in which cells stop dividing. However, unlike permanently senescent cells, these drug-tolerant cells regained their ability to grow once the treatment was withdrawn. This suggested that the surviving cells exhibited reversible behavior and remained capable of restarting tumor growth, which may contribute to relapse.

These cells adapted by reshaping their metabolism and altering lysosome-associated functions, which are involved in nutrient processing and waste recycling. In particular, they became highly dependent on glutamine metabolism and lysosome-associated functions to survive during KRAS inhibition.

The researchers suggest that these findings open the door to a combination treatment strategy in which KRAS inhibitors first suppress the main tumor population, while additional therapies target the survival mechanisms that persister cells depend on, including altered glutamine metabolism and lysosome-associated functions.

"If such a strategy becomes available in clinical practice, patients with KRAS-mutant cancers may receive treatment regimens designed not only to shrink tumors, but also to prevent relapse by eliminating residual cancer cells," says Dr. Aoki. "In 5 to 10 years, this could help move KRAS-targeted therapy toward a more complete and potentially curative cancer treatment."

Although still at an early stage, the findings point to a potential strategy for improving treatment outcomes in KRAS-mutant cancers, which were once considered exceptionally difficult to target.

Source:

Chiba University

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