The multiple myeloma (MM) mutational landscape has identified alterations in KRAS as the most recurring somatic variant. 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 that 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 have used AZD4785, a potent and selective antisense oligonucleotide (ASO) which selectively targets and down-regulates 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, confirming KRAS as a driver and a therapeutic target in MM.Copyright © 2021 American Society of Hematology.
About The Expert
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
Robert A MacLeod
Brandon Stephen Willis
Hongbo Cai
Joana Hauser
Claire Rooney
Sophie Elizabeth Willis
Philip L Martin
Anna Dominika Staniszewska
Helen Ambrose
Lyndsey Hanson
Chiara Cattaneo
Alessandra Tucci
Giuseppe Rossi
Roberto Ronca
Antonino Neri
Stefania Mitola
Niccolo Bolli
Marco Presta
Michele Moschetta
Sarah Ross
Aldo M Roccaro
References
PubMed