A major new review published in the high-impact Nature journal Signal Transduction and Targeted Therapy (impact factor >50) is reshaping the conversation around KRAS, one of the most historically “undruggable” oncogenes in human cancer. The article, “Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges,” led by researchers at the Barbara Ann Karmanos Cancer Institute and Wayne State University, has rapidly gained international attention, becoming one of the most accessed papers in the journal, earning an Altmetric score of 33, and being highlighted among the Top 10 oncology articles of the week by OncoDaily News; a clear sign of its scientific and clinical impact.
KRAS mutations lie at the heart of some of the world’s deadliest malignancies, especially pancreatic ductal adenocarcinoma (PDAC), colorectal cancer and lung cancer. For decades, KRAS eluded every attempt at therapeutic targeting because its protein surface lacked exploitable binding pockets, cementing its reputation as “undruggable.” Only in the last few years has that perception shifted, following the discovery of the switch-II pocket in KRAS-G12C and the development of the first direct inhibitors. While these drugs validated that KRAS can indeed be targeted, their modest response rates and limited durability highlight the need for next-generation strategies, especially for KRAS mutations prevalent in PDAC, such as G12D and G12V.
According to the corresponding author, Asfar Azmi, Ph.D., professor, director of Pancreas Cancer Research, and member of the Molecular Therapeutics (MT) Research Program, this article reflects a pivotal turning point for the field.
“For decades, KRAS symbolized everything we could not achieve in cancer therapy. This review makes it clear that the scientific landscape has undergone a fundamental shift. With advances in chemistry, structural biology, tumor immunology, and microenvironmental science, KRAS is now a tractable therapeutic target. The path forward lies in mutation-specific precision and rationally designed combinations that can deliver truly durable responses.”
Dr. Azmi emphasized the ongoing translational efforts in his laboratory at Karmanos, where multiple combination strategies are currently under active investigation. These include pairing KRAS inhibitors with agents targeting proliferating cell nuclear antigen (PCNA), p21-activated kinase 4 (PAK4), and exportin-1 (XPO1). Each approach is designed to counter adaptive resistance pathways and deepen the magnitude and duration of KRAS inhibitor responses in pancreatic and other KRAS-driven malignancies. Together, these efforts aim to establish a next-generation therapeutic framework in which KRAS inhibition becomes not only feasible but also meaningfully transformative for patients.
Khalil Choucair, M.D., MSc, the first author of this review, medical oncologist, assistant professor of Oncology, member of the Thoracic Oncology, Phase I Clinical Trials Multidisciplinary Teams (MDT) and the MT Research Program, highlighted that the goal of this review was to provide a balanced, yet forward-looking synthesis of the field.
“G12C inhibitors proved the fundamental concept that direct KRAS targeting is possible. However, the next phase requires us to overcome resistance, broaden efficacy to these drugs, and integrate therapeutic strategies that reflect tumor evolution, lineage plasticity, and microenvironmental forces,” he said. “The pace of progress in KRAS biology and drug development has never been faster, and this review captures both the momentum and the scientific maturity now driving the field forward. Such efforts, as summarized in our work, stand as proof of the power of research to advance clinical care and translate into new hope to our patients on their journey.”
“A major fraction of the KRAS therapeutics discussed in this review, including KRAS-G12C inhibitors, emerging KRAS-G12D inhibitors, pan-RAS drugs, and KRAS-targeted vaccines, are already being offered or are available through clinical trials at Karmanos. We are not just analyzing the field, we are directly implementing the most advanced KRAS-targeted approaches in our patient population,” explained Najeeb Al Hallak, M.D., MS, medical oncologist, co-leader of the Gastrointestinal and Neuroendocrine Oncology, and member of the Phase I Clinical Trials MDT and the MT Research Program.
“The fact that this review has become one of the most accessed papers in the journal, has earned a strong Altmetric score, and was featured among the Top 10 articles in OncoDaily News speaks to its importance,” said Boris Pasche, M.D., Ph.D., FACP, president and CEO of Karmanos. “It underscores Karmanos’ leadership in translational oncology and our commitment to addressing the most challenging problems in cancer research. KRAS has been considered impenetrable for decades, and our team is now helping define the strategies that will change that.”
As the field moves toward broad-spectrum KRAS inhibition, addressing G12D, G12V, and even pan-RAS signaling with RNA-based modalities, PROTAC degraders, immune-based approaches, and rationally designed combinations, the narrative around KRAS is undergoing a historic shift. Karmanos stands prominently at the forefront of this transformation, both through scholarship and through active clinical trials that are already reaching patients.
Learn more about the gastrointestinal and neuroendocrine clinical trials available at Karmanos, including trials for pancreatic cancer, and the Molecular Therapeutics Research Program at kamranos.org.