TY - JOUR
T1 - Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited antitumor activity
AU - Sacco, Antonio
AU - Federico, Cinzia
AU - Todoerti, Katia
AU - Ziccheddu, Bachisio
AU - Palermo, Valentina
AU - Giacomini, Arianna
AU - Ravelli, Cosetta
AU - Maccarinelli, Federica
AU - Bianchi, Giada
AU - Belotti, Angelo
AU - Ribolla, Rossella
AU - Favasuli, Vanessa
AU - Revenko, Alexey S.
AU - Macleod, A. Robert
AU - Willis, Brandon
AU - Cai, Hongbo
AU - Hauser, Joana
AU - Rooney, Claire
AU - Willis, Sophie E.
AU - Martin, Philip Lloyd
AU - Staniszewska, Anna
AU - Ambrose, Helen
AU - Hanson, Lyndsey
AU - Cattaneo, Chiara
AU - Tucci, Alessandra
AU - Rossi, Giuseppe
AU - Ronca, Roberto
AU - Neri, Antonino
AU - Mitola, Stefania
AU - Bolli, Niccolò
AU - Presta, Marco
AU - Moschetta, Michele
AU - Ross, Sarah
AU - Roccaro, Aldo M.
N1 - Funding Information:
This work was supported by AstraZeneca (Cambridge, United Kingdom), the European Hematology Association, Italian Association for Cancer Research (AIRC) grant IG 24689, the Fondazione Regionale per la Ricerca Biomedica, Transcan-2 ERA-NET, and the Associazione Italiana Contro le Leucemie-Linfomi e Mieloma Brescia (A.M.R.); by AIRC grant IG 16722 and the Italian Ministry of Health (Ricerca Corrente 2019) (A.N.); Fondazione Cariplo grant 2016-0570 (A.G.); AIRC grant IG 2019-ID.23151 (R. Ronca); by a fellowship from Fondazione Veronesi (F.M.); and by grant 817997 from the European Research Council under the EU Horizon 2020 Research and Innovation Programme (N.B.).
Funding Information:
Conflict-of-interest disclosure: A.M.R. reports research funding from AstraZeneca, the European Hematology Association, Transcan-2 ERA-NET, and the Italian Association for Cancer Research and honoraria from Amgen, Celgene, and Janssen. N.B. reports honoraria from Amgen, Celgene, and Janssen. A.S.R. and R.M. are employees and shareholders of Ionis Pharmaceuticals. B.W., H.C., C. Rooney, S.E.W., P.L.M., M.M., H.A., A. StaniszewskaSt., L.H., and S.R. are employees and shareholders of AstraZeneca Pharmaceuticals. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/11/4
Y1 - 2021/11/4
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2020010572
DO - 10.1182/blood.2020010572
M3 - Article
C2 - 34077955
AN - SCOPUS:85116199517
VL - 138
SP - 1705
EP - 1720
JO - Blood
JF - Blood
SN - 0006-4971
IS - 18
ER -