KRAS-targeting drugs show promise for rare appendix cancer

UT MD Anderson Research News July 12, 2026

• KRAS is the most common genetic mutation in appendix cancer, occurring in approximately 80% of mucinous tumors, the most common subtype
• KRAS-targeted therapies demonstrate robust activity in early preclinical and clinical data
• Most patients experienced clinical benefit with rapid biomarker decline

Targeting mutant KRAS may offer a promising new treatment option for appendix cancer, according to research from The University of Texas MD Anderson Cancer Center published in the Journal of Hematology & Oncology.

Researchers led by John Paul Shen, M.D., assistant professor, Saikat Chowdhury, Ph.D., instructor, and Ichiaki Ito, Ph.D., research scientist, all of Gastrointestinal Medical Oncology, demonstrated that KRAS inhibitors significantly reduced tumor growth, blocked key cancer signaling pathways and triggered cancer cell death in advanced preclinical models of appendiceal adenocarcinoma. In a clinical cohort of 15 patients treated with a variety of different KRAS drugs, all evaluable patients experienced a marked reduction in serum tumor markers – the most effective measure of response in appendix cancer.

“Appendiceal cancer has long lacked effective systemic treatment options, and patients urgently need new approaches,” Shen said. “I am very excited about the future prospects of KRAS inhibition. This study is just the first step.”

What is KRAS and how can it be targeted to treat cancer?
KRAS is one of the most frequently mutated cancer-driving genes in solid tumors, including pancreatic, colorectal, lung and appendiceal cancers. For decades, KRAS was considered “undruggable” due to a lack of clear drug-binding sites and its ability to shift between structural states.

Recent scientific advances have led to the development of therapies that directly inhibit specific forms of mutant KRAS, including KRAS G12C inhibitors such as sotorasib and adagrasib. These agents have demonstrated clinical benefits in select patients and represent a significant advancement in precision oncology.

Next-generation therapies are now being developed to target a broader range of mutant KRAS. These include pan-RAS (ON) inhibitors, such as daraxonrasib, which have shown promising activity across multiple KRAS-mutant cancers. In this study, investigators evaluated a range of KRAS-targeted therapies, including daraxonrasib and the G12D-selective inhibitor MRTX1133.

What are other key findings about KRAS and appendix cancer in this study?
The study revealed that key appendix cancer markers decreased rapidly in patients, with an average reduction of more than 80% within the first 12 weeks of treatment. Further, responses were observed across both high- and low-grade tumors, varied KRAS mutations, and different KRAS inhibitor therapies.

How could this research shape future treatments for appendix cancer?
In addition to showing clinical benefit, the study also investigated how appendix cancers may adapt to treatment with KRAS inhibitors over time. Cancer cells activated alternative pathways associated with resistance, and changes in the tumor microenvironment suggested potential opportunities to improve outcomes by combining KRAS inhibitors with other therapies, such as immunotherapy or anti-angiogenic treatments. 

While these results are based on a small cohort of patients in early-phase trials, the findings support larger prospective trials and position KRAS inhibition as a promising new direction for patients with appendix cancer.

***

This research was supported by the Col. Daniel Connelly Memorial Fund, the Andrew Sabin Family Fellowship, the Cancer Prevention and Research Institute of Texas (CPRIT) and the Appendix Cancer Pseudomyxoma Peritonei Research Foundation (ACPMP). A full list of collaborating authors and their disclosures can be found with the paper in the Journal of Hematology & Oncology.