Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second most common cause of death within the next 10 years. The prognosis for this disease is poor despite diagnostic progress and new chemotherapeutic regimens. The oncogenic KRAS mutation is the major event in pancreatic cancer; it confers permanent activation of the KRAS protein, which acts as a molecular switch to activate various intracellular signalling pathways and transcription factors inducing cell proliferation, migration, transformation and survival. Several laboratory methods have been developed to detect KRAS mutations in biological samples, including digital droplet PCR (which displays high sensitivity). Clinical studies have revealed that a KRAS mutation assay in fine-needle aspiration material combined with cytopathology increases the sensitivity, accuracy and negative predictive value of cytopathology for a positive diagnosis of pancreatic cancer. In addition, the presence of KRAS mutations in serum and plasma (liquid biopsies) correlates with a worse prognosis. The presence of mutated KRAS can also have therapeutic implications, whether at the gene level per se, during its post-translational maturation, interaction with nucleotides and after activation of the various oncogenic signals. Further pharmacokinetic and toxicological studies on new molecules are required, especially small synthetic molecules, before they can be used in the therapeutic arsenal for pancreatic ductal adenocarcinoma.

Key points

  • The major genetic event in pancreatic ductal adenocarcinoma is the activating point mutation of the KRAS oncogene; the KRAS protein becomes permanently activated, consequently maintaining the cellular processes of proliferation, transformation, invasion and survival.

  • Detection of KRAS mutations can be performed in a variety of biological samples including fresh and fixed tumour tissue or biopsy samples, fine-needle aspiration materials and cytological samples, and in total blood and plasma.

  • The KRAS mutation assay can be combined with endoscopic ultrasonography-guided cytopathology to increase the sensitivity, the negative predictive value and accuracy of cytopathology alone for the positive diagnosis of pancreatic cancer and its differential diagnosis with chronic pancreatitis.

  • The presence of mutated KRAS correlates with a worse prognosis for patients with pancreatic cancer whether or not they undergo curative surgery. KRAS mutation assays could provide important predictive information on tumour progression and recurrence.

  • Mutated KRAS might be targeted therapeutically, especially at the gene level and during its post-translational maturation; the interactions between KRAS proteins and adaptor proteins or nucleotides and downstream oncogenic signals might also be targeted.

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Fig. 1: Activation of KRAS protein and its downstream intracellular pathways.
Fig. 2: KRAS mediates tumour cell reprogramming and interactions with the surrounding microenvironment.
Fig. 3: Different therapeutic strategies targeting the KRAS gene and KRAS protein.

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Acknowledgements

The authors thank E. Buscail for his helpful advice on liquid biopsies in cancer.

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L.B. and P.C. researched data for the article, made a substantial contribution to discussion of content, and wrote and reviewed/edited the manuscript before submission. B.B. researched data for the article, made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission.

Correspondence to Louis Buscail.

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Buscail, L., Bournet, B. & Cordelier, P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-019-0245-4

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