KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Claudio Luchini, Gaetano Paolino, Paola Mattiolo, Maria L. Piredda, Alessandro Cavaliere, Marina Gaule, Davide Melisi, Roberto Salvia, Giuseppe Malleo, Jae Il Shin, Sarah Cargnin, Salvatore Terrazzino, Rita T. Lawlor, Michele Milella, Aldo Scarpa

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24 Citations (Scopus)


Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases. The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group. This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.

Original languageEnglish
Article number227
JournalJournal of Experimental and Clinical Cancer Research
Issue number1
Publication statusPublished - 2020 Dec 1

Bibliographical note

Funding Information:
This study is supported by Associazione Italiana Ricerca sul Cancro (AIRC 5 × 1000 n. 12182) and Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017). Acknowledgements Ethics approval and consent to participate, consent for publication

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research


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