Specific targeting of KRAS using a novel antisense oligonucleotide exerts anti-tumor activity in multiple myeloma

The multiple myeloma (MM) mutational landscape has identified alterations in KRAS as the most recurring somatic variant. Combining DNA and RNA sequencing, 756 patients were studied, and KRAS was observed as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence or the KRAS aberration at disease relapse. After several decades of effort, small molecule inhibitors targeting KRAS have emerged and are showing promising activity in clinical trials. However, these inhibitors are selective for tumors carrying that KRASG12C mutation and will only treat a subset of patients, predominantly with lung or colon tumors where this mutation is most prevalent. Therefore, there is still a need to develop novel therapeutic approachesto target the KRAS mutational events found in other tumor types, including MM. AZD4785, is a potent and selectivetherapeutic antisense oligonucleotide (ASO), tested in phase I clinical trials, which selectively targets and down-regulates all KRAS isoforms. Therefore, we explored the activity of AZD4785 in MM models, demonstrating its ability to strongly down-regulate KRAS andto inhibit the growth of MM cells, both in vitro and in vivo, confirming KRAS as a driver and a therapeutic target in MM. Human MM Cell Lines (HMCLs), MM.1S, KMS20 (KRAS mutated), OPM2 (KRAS WT) and U266 (BRAF mutated), were analyzed after 3 µM AZD4785 exposure for 48 hours in comparison to untreated HMCL samples. Each cell line was considered in triplicates for each condition.