Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited antitumor activity

Antonio Sacco, Cinzia Federico, Katia Todoerti, Bachisio Ziccheddu, Valentina Palermo, Arianna Giacomini, Cosetta Ravelli, Federica Maccarinelli, Giada Bianchi, Angelo Belotti, Rossella Ribolla, Vanessa Favasuli, Alexey S. Revenko, A. Robert Macleod, Brandon Willis, Hongbo Cai, Joana Hauser, Claire Rooney, Sophie E. Willis, Philip Lloyd MartinAnna Staniszewska, Helen Ambrose, Lyndsey Hanson, Chiara Cattaneo, Alessandra Tucci, Giuseppe Rossi, Roberto Ronca, Antonino Neri, Stefania Mitola, Niccolò Bolli, Marco Presta, Michele Moschetta, Sarah Ross, Aldo M. Roccaro

Research output: Contribution to journalArticlepeer-review

Abstract

Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM.

Original languageEnglish
Pages (from-to)1705-1720
Number of pages16
JournalBlood
Volume138
Issue number18
DOIs
Publication statusPublished - Nov 4 2021

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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