RMC-7977 a broad RAS inhibitor increases the sensitivity towards Bortezomib

The drug Bortezomib commonly treats patients with multiple myeloma. However, its use is more limited in other cancers, such as hepatocellular and cervical cancer. Additionally, reports have indicated cases of resistance to Bortezomib. In this context, studies have demonstrated that Ras signaling plays a significant role in influencing the sensitivity of cancer cells to chemotherapeutic drugs. A new experimental drug called RMC-7977 was made by Revolution Medicines. It targets the active, GTP-bound forms of RAS proteins, such as KRAS, NRAS, and HRAS. Since RMC-7977 is a broad Ras inhibitor recently discovered, we sought to evaluate its efficacy in enhancing the sensitivity of cancer cells to Bortezomib. Our study aimed to assess the effect of RMC-7977 on Bortezomib sensitivity. The results show that HeLa and HepG2 cells exhibit lower sensitivity to Bortezomib compared to RPMI-8266 cells. However, combination therapy with RMC-7977 and Bortezomib increases the sensitivity of HeLa and HepG2 cells to Bortezomib. Cycloheximide has a big effect on the levels of Ras protein in RPMI-8266 cells, but it doesn't change them at all in HeLa and HepG2 cells. These findings underscore the crucial role of Ras signaling in determining sensitivity to Bortezomib. The present study also highlights the potential of the RMC-7977 inhibitor in enhancing the response to Bortezomib. This work could broaden the scope of FDA-approved Bortezomib to include additional cancers beyond multiple myeloma and improve outcomes for patients with chemoresistant multiple myeloma. Furthermore, it may open up new therapeutic applications for the recently discovered RMC-7977.