Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, largely driven by mutations in the KRAS gene—once considered impossible to target. Among them, the KRAS G12D mutation fuels unchecked tumor growth, immune escape, and treatment resistance. But a scientific shift is underway. Latest breakthroughs in targeting KRAS, including promising drugs like MRTX1133 and RMC-9805, as well as novel approaches that combine targeted therapy with immunotherapy or metabolic intervention are underway. By unraveling the complexities of KRAS biology and resistance mechanisms, researchers aim to open new treatment avenues for a cancer long known for its grim prognosis.
Accounting for nearly 90% of all pancreatic cancers, pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of just 13%. Late-stage diagnosis, limited surgical options, and toxic chemotherapy regimens contribute to its poor outcomes. Over 90% of PDAC cases harbor KRAS mutations, with KRAS G12D as the most common variant. These mutations drive aggressive tumor behavior and have resisted conventional drug design for decades. Although other cancers have seen progress through precision medicine, PDAC remains stubbornly difficult to treat. Due to these challenges, there is a pressing need to explore new therapeutic strategies targeting KRAS and its downstream effects to improve outcomes for patients facing this formidable disease.
A research team from Xinjiang Medical University and Shenzhen University has released a comprehensive review (DOI: 10.20892/j.issn.2095-3941.2025.0122) in Cancer Biology & Medicine on July 7, 2025, outlining major advances in the fight against KRAS-driven pancreatic cancer. Long viewed as an "undruggable" target, KRAS is finally yielding to innovative therapies. The review charts the progress of next-generation KRAS inhibitors, resistance pathways, and synergistic treatment strategies, offering new hope for patients and clinicians. It marks a moment in precision oncology's effort to confront one of the toughest challenges in cancer treatment.
The review presents a sweeping analysis of KRAS mutations in PDAC, focusing on how they promote tumor growth, metabolic rewiring, and immune suppression. It places special emphasis on the KRAS G12D mutation, which appears in 40% of cases and has historically eluded drug targeting. Breakthrough agents like MRTX1133 and RMC-9805 are changing that narrative—MRTX1133 shows over 85% tumor shrinkage in preclinical models, while RMC-9805 has demonstrated significant efficacy in early trials. Beyond mutation-specific inhibitors, the review explores emerging tools like PROTAC-based degraders, siRNA delivery systems, and pan-KRAS inhibitors. However, drug resistance remains a critical obstacle, with tumors finding ways to reactivate signaling pathways or shift cellular states through epithelial-to-mesenchymal transition. To address this, researchers are turning to combination therapies involving MEK, PI3K, or CDK4/6 inhibitors, as well as immunotherapy approaches. Early clinical data—such as a 33% partial response rate to adagrasib in KRAS G12C -mutant PDAC—suggest that a layered approach may provide the best outcomes. Together, these findings lay a roadmap for tackling KRAS mutations not just as a molecular target, but as the central node in a complex and adaptive cancer network.
"KRAS has long been one of cancer's most elusive enemies," said Dr. Wenting Zhou, corresponding author of the review. "But we're now seeing real momentum—from understanding how KRAS mutations reshape tumor biology to designing drugs that can outsmart them. What excites me most is the convergence of multiple strategies—targeted inhibitors, immune-based therapies, and metabolic disruption. This multi-pronged approach has the potential to not just slow the disease but fundamentally change how we treat pancreatic cancer."
These advances in KRAS-targeted therapy could usher in a new era for pancreatic cancer treatment. For the first time, patients with advanced, inoperable PDAC may benefit from drugs that directly attack the cancer's molecular engine. When combined with immunotherapy or agents that suppress compensatory pathways, KRAS inhibitors may also prevent or delay resistance. Though many approaches are still in early clinical trials, their success could pave the way for broader use in other RAS-driven cancers. More broadly, this research reinforces the importance of personalized medicine—tailoring treatment based on each tumor's genetic makeup—to improve survival and quality of life for patients facing one of the world's deadliest cancers.
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References
DOI
10.20892/j.issn.2095-3941.2025.0122
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0122
Funding information
The study was supported by the Tianshan Talents-Youth Science and Technology Innovation Talents Training Program of Xinjiang Autonomous Region (Grant No. 2022TSYCCX0035), the Xinjiang Key Laboratory of Natural Medicines Active Components and Drug Release Technology (Grant No. XJDX1713), the "Fourteenth Five-Year Plan" Key Discipline Construction Project of Xinjiang Autonomous Region (2021), the Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education (2023), and the Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices (2023)..
About Cancer Biology & Medicine
Cancer Biology & Medicine ( CBM ) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world.
Cancer Biology & Medicine
Not applicable
Drugging the 'undruggable' KRAS: breakthroughs, challenges, and opportunities in pancreatic cancer
7-Jul-2025
The authors declare that they have no competing interests.