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

Caitlin A McIntyre ¹, Adrien Grimont ², Jiwoon Park ³

¹Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
⁴Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
⁵Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada.
⁷Marie-Josee and Henry R Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁸Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁹Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
¹⁰Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹¹Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
¹²Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
¹³Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁴Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
¹⁵Department of Pathology, Weill Cornell Medicine, New York, NY, USA.
¹⁶Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁷Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA; WorldQuant Initiative for Quantitative Prediction, Weill Cornell Medicine, New York, NY, USA.
¹⁸Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁹Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY, USA.

⁰Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Cancer Cell +

|

August 30, 2024

View abstract on PubMed

Summary

KRAS mutations in pancreatic cancer (PDAC) impact patient outcomes. KRAS<sup>G12R</sup> is linked to early-stage disease and better survival, while KRAS<sup>G12D</sup> shows distinct biological signaling.

Area Of Science

Oncology
Molecular Biology
Genetics

Background

KRAS mutations are common in pancreatic ductal adenocarcinoma (PDAC).
The varying oncogenicity of different KRAS mutations in PDAC and their clinical implications require deeper investigation.
Understanding mutation-specific biology is crucial for targeted therapies.

Purpose Of The Study

To explore the clinical and biological differences between KRAS<sup>G12R</sup> and KRAS<sup>G12D</sup> mutations in pancreatic ductal adenocarcinoma (PDAC).
To investigate the prognostic value of specific KRAS mutations in PDAC patients undergoing surgical resection.

Main Methods

Analysis of 1,360 PDAC patients undergoing surgical resection.
Spatial profiling of 20 PDAC tumors and bulk RNA-sequencing of 100 PDAC tumors.
Orthogonal studies using mouse Kras<sup>G12R</sup> PDAC organoids and orthotopic models.

Main Results

KRAS<sup>G12R</sup> mutations were enriched in early-stage (Stage I) PDAC, associated with node-negativity, decreased distant recurrence, and improved survival compared to KRAS<sup>G12D</sup>.
KRAS<sup>G12D</sup> tumors exhibited enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT).
KRAS<sup>G12R</sup> tumors showed increased nuclear factor κB (NF-κB) signaling, decreased migration, and improved survival in mouse models.

Conclusions

KRAS alterations in PDAC are associated with distinct clinical presentations, outcomes, and biological behaviors.
Specific KRAS mutations have significant prognostic value in PDAC.
Articulating mutation-specific PDAC biology is essential for advancing treatment strategies.

Keywords:

KRAS clinical outcomes genomics organoids pancreatic cancer spatial transcriptomics

Related Concept Videos

The <em>Ras</em> Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...