Myeloma Novel Drug Targets and agents
Category: Myeloma Novel Drug Targets and agents
Preclinical activity of pharmacological inhibitors targeting KRAS and pan-RAS in multiple myeloma
Torsten O. Steinbrunn, MD, PhD
Attending Physician
Department of Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
RAS mutations are among the most frequent oncogenic drivers of both solid tumors and hematologic malignancies. In particular, point mutations in codons 12, 13, and 61 disrupt the intrinsic GTPase activity of RAS proteins, resulting in constitutive activation of key survival and proliferation pathways, including those signaling via MEK/MAPK and PI3K/AKT. Recently, KRAS G12C-specific inhibitors have demonstrated clinical efficacy in solid tumors such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). However, their narrow mutation specificity limits the relevance in hematologic malignancies like multiple myeloma (MM). In contrast, novel KRAS- and pan-RAS-targeting inhibitors with broader activity profiles may offer therapeutic potential for a wider subset of MM patients.
Methods:
We assessed the distribution of KRAS and NRAS point mutations in MM, based on genomic data from n=992 patients in the CoMMpass study (MMRF release IA22). Additionally, we evaluated the activity of the KRAS-specific small molecule inhibitor BI-2865 and the pan-RAS (RAS-ON) inhibitor RMC-6236 in a panel of RAS-mutant MM cell lines. Cellular responses were measured using proliferation and viability assays (CTG).
Results:
Unlike NSCLC and CRC, where KRAS codon 12 mutations predominate (89% and 65%, respectively), MM exhibits a distinct mutational landscape, with codon 61 mutations being most frequent in both KRAS (37%) and NRAS (70%), followed by mutations in codons 12 and 13. The KRAS-specific inhibitor BI-2865 showed selective activity preferentially in MM lines harboring KRAS codon 12 mutations. The pan-RAS inhibitor RMC-6236 demonstrated different levels of activity across MM lines with various KRAS and NRAS mutations, including those in codons 12, 13 and 61.
Conclusions:
Novel pharmacological KRAS and pan-RAS inhibitors with broader activity profiles show promising efficacy against RAS-mutated MM lines. These agents may significantly extend the therapeutic relevance of RAS-targeted therapies in MM, ultimately offering new therapeutic approaches for a larger number of MM patients.