In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRAS^G12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

01 Sep 2024·Cancer Cell

Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer

Article

Author: Sisso, Whitney J. ; Houlihan, Shauna L. ; Jarnagin, William R. ; Park, Wungki ; Ecker, Brett L ; Schultz, Nikolaus ; Meng, Yinuo ; McIntyre, Caitlin A ; Houlihan, Shauna L ; Chandwani, Rohit ; Chan, Christopher W ; Church, George M. ; Seier, Kenneth ; Grimont, Adrien ; Falvo, David J ; Pulvirenti, Alessandra ; Church, George M ; Falvo, David J. ; McIntyre, Caitlin A. ; Aveson, Victoria G. ; Jang, Gun Ho ; Sisso, Whitney J ; O'Reilly, Eileen M ; Zafra, Maria Paz ; Mason, Christopher E ; Chan, Christopher W. ; Dow, Lukas E. ; Mason, Christopher E. ; Jarnagin, William R ; Fall, William B. ; Notta, Faiyaz ; Wenger, Andrew ; Aveson, Victoria G ; Park, Jiwoon ; Gonen, Mithat ; Fall, William B ; Walch, Henry ; Hissong, Erika ; Dow, Lukas E ; Siolas, Despina ; Ecker, Brett L. ; Gelfer, Rebecca ; Alonso, Alicia ; O’Reilly, Eileen M.

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRAS^G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS^G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRAS^G12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRAS^G12D and increased nuclear factor κB (NF-κB) signaling in KRAS^G12R tumors. Orthogonal studies of mouse Kras^G12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.

01 Oct 2021·Journal of Pancreatic Cancer

Cobimetinib Plus Gemcitabine: An Active Combination in KRAS G12R-Mutated Pancreatic Ductal Adenocarcinoma Patients in Previously Treated and Failed Multiple Chemotherapies

Article

Author: Sleeman, Danny ; Azqueta, Jose ; Ardalan, Bach

Purpose: The KRAS proto-oncogene is involved in the RAS/MAPK pathway. KRAS is present in the wild type or mutated forms. The oncogene KRAS is frequently mutated in various cancers. At the time that amino acid glycine is mutated, KRAS protein acquires oncogenic properties that result in the tumor cell growth, proliferation, and cancer progression. There has been limited understanding of the different mutations at codon 12. The consequences of such mutations is not fully understood. Various G12X mutations in pancreatic cancer patients have been examined, with the most common mutations being G12D (40%), G12V (30%), and G12R (15-20%). Now we are understanding that G12X mutations in the KRAS are not all equal. Methods: In a single-arm exploratory study, we accrued 13 KRAS-G12X-mutated pancreatic patients (KRAS G12D, G12V, and G12R). They were divided into two groups: group 1 consisted of seven patients with G12D and G12V and group 2 included six patients with the KRAS G12R mutation. All patients were treated with the combination of gemcitabine at 1250 mg/m² intravenous weekly for 3 weeks and oral cobimetinib 20 mg b.i.d. for 3 weeks. This was followed by a week of rest before the initiation of the next cycle. Results: In the first cohort, seven patients were on treatment, all of whom progressed and died within the 2 months of the study. In the second cohort, one of six patients achieved partial response, and five achieved stable disease. Median progression-free survival was 6 months (9% confidence interval 3.0-9.3 months) and overall survival has been reached at 8 months. Common adverse reactions included rash, fatigue, nausea, and vomiting (grades 2 and 3). Cancer antigen CA19-9 decreased by >50% in all group 2 patients. Conclusion: Our pancreatic cancer patients were heavily pretreated (all had received FOLFIRINOX and gemcitabine/nab-paclitaxel) before the entry into our trial. Upon entry into our trial, all patients were treated with the combination of gemcitabine and oral cobimetinib. Therefore, this constituted the second exposure of the patients to gemcitabine. This study illustrates a new discovery, which can potentially target 15-20% of pancreatic cancer patients and allow for a significant improvement in their prognosis. We will be conducting randomized phase II trials to substantiate our findings.

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