Kirsten rat sarcoma virus (KRAS) oncoprotein as a new therapeutic target in multiple myeloma

Kirsten rat sarcoma virus (KRAS) gene, a member of the well-known RAS oncogene family, has been identified in a wide variety of malignant diseases and plays a crucial role in oncogenesis and progression. KRAS mutations have been strongly associated with shorter overall and progression-free survival in many different malignant diseases, including multiple myeloma (MM). Multiple myeloma (MM) is a malignant plasma cell disorder ranked as the second most common blood cell malignancy. Clinically, it manifests as anemia, renal damage, skeletal lesions, and a high frequency of infections, often resulting in death. Despite significant progress in treatment such as immunotherapeutic drugs, proteasome inhibitors, and apoptosis inhibitors, MM remains incurable due to the development of drug resistance in patients. The overall survival rate is approximately 60% at 5 years, highlighting the urgent need for new and affective agents. At least 20% of MM patients have been reported to carry KRAS point mutations. Therefore, targeting the KRAS oncoprotein provides a potential therapeutic strategy in MM. Early evidence revealed that down-regulation of KRAS using siRNA inhibited MM tumor growth both in vitro and in vivo. Daraxonrasib (RMC6236), an FDA-approved small molecule pan-Ras (ON) state inhibitor, has shown anti-tumor activity in U.S. clinical trials. In this study, we evaluated the anti-myeloma activity of RMC6236 in MM cells. Our results showed that RMC6236 inhibited cell growth in a dose response manner across different MM cell subtypes, including both KRAS mutant and wild-type (WT) cells. Depending on the KRAS genotype mutational status, the IC50 of RMC6236 was estimated to range from 20 to 800 nM, Also, cell cycle assays revealed that RMC6236 treatment significantly decreased the number of cells in S phase (DNA synthesis), suggesting an inhibition of cell cycle progression in MM cells. Moreover, combining RMC6236 with anti-myeloma agent venetoclax or a novel anti-PCNA agent AOH1996 significantly reduced cell growth in KRAS mutant and WT MM cells. RT-qPCR assays revealed that RMC6236 treatment led to decreased gene expression of KRAS, CSC signature markers, anti-apoptotic markers, IL-6, STAT3, and mTOR in MM cells, along with the down-regulation of EZH2 and MEK/ERK signal pathways. These findings suggest that the inhibition of MM cell growth by RMC6236 may be linked to the down-regulation of these tumor-associated genes. Ongoing studies aim to further evaluate the anti-myeloma potential of RMC6236.