A first-in-class RNA degrader reduces c-MYC expression and myeloma cell survival in preclinical models
Abstract
The c-MYC (MYC) oncogene is a critical driver of multiple myeloma (MM), however, direct targeting of the MYC protein has proven challenging due to its intrinsic structural disorder. In this study, we evaluated the biological activity and molecular mechanism of a ribonuclease-targeting chimera (RiboTAC) designed to promote the degradation of MYC mRNA (MYC-RiboTAC) across a panel of primary patient MM samples and MM cell lines. This heterobifunctional molecule consists of a small molecule targeting the MYC internal ribosomal entry site (IRES) conjugated to a small-molecule recruiter of endogenous RNaseL. The MYC-RiboTAC reduces MYC mRNA and protein levels in an RNase L-dependent manner, selectively inhibits MYC-driven transcriptional programs, and exhibits potent anti-MM activity. It effectively suppresses cell growth in MM cells co-expressing MYC and RNase L, even in the presence of the protective bone marrow. Furthermore, it synergizes with clinically active agents such as carfilzomib, lenalidomide, and pomalidomide. Importantly, MYC-RiboTAC displays favorable safety and pharmacokinetic profiles in mice and significantly suppresses tumor growth in NOD SCID mice bearing MM xenografts, as shown in two different models. These findings highlight the potential of RNA degraders to target mRNAs encoding "undruggable" proteins such as MYC, offering a promising avenue for precision cancer therapy
Article Details
Authors (29)
Domenico Maisano
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States
Tenghui Wang
Skaggs Graduate School of Chemical and Biological Sciences
Steffen Benham Kulp
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School. 02215 Boston, MA, United States
Vanessa Katia Favasuli
Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy
Yuquan Tong
The Scripps Research Institute, Department of Chemistry, 130 Scripps Way, Jupiter, Florida 33458, United States
Michela Cumerlato
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, United States
Chungen Li
Francesca Barello
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, United States
Marcello Turi
Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Paola Rampa
INOC - Istituto Nazionale Oncologico Candiolo, Candiolo (TO), Italy
Rosa Alba Parisi
Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy
Filip Garbicz
Francesco Ladisa
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States
Giulia Giorgetti
Clinic of Hematology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa, Italy
Chandraditya Chakraborty
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States
Laure Vreux
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States
Valentina Sangiorgio
Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO), Italy
Ivana Sarotto
Candiolo Cancer Institute FPO-IRCCS, Candiolo, Italy
Anil Aktas Samur
Dana Farber Cancer Institution, Boston, Massachusetts, United States
Mehmet K. Samur
Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts, United States
Ruben D. Carrasco
Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, United States
Mariateresa Fulciniti
Dana Farber Cancer Institute, Boston, Massachusetts, United States
Michael D Cameron
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, United States
Kenneth C. Anderson
Annamaria Gulla
Istituto nazionale Oncologico Candiolo INOC, Candiolo, Italy
Jessica Childs-Disney
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Department of Chemistry, Jupiter, Florida, United States
Matthew D. Disney
Department of Chemistry, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, 130 Scripps Way, Jupiter, Florida 33458, United States
Eugenio Morelli
INOC - Istituto Nazionale Oncologico Candiolo, Candiolo, Italy
Nikhil C. Munshi