Exploring Intracellular Signaling Responses to KS18, a Potent Mcl-1 Inhibitor, in Multiple Myeloma

Multiple myeloma (MM), a cancer of plasma B cells, is a hematological malignancy in which patients inevitably relapse and develop drug resistance. Mcl-1, a member of the anti-apoptotic subgroup of Bcl-2 family proteins, plays a critical role in the progression of multiple myeloma and contributes significantly to drug resistance. Elevated Mcl-1 expression is observed in approximately 52% of MM patients at diagnosis, increasing to 81% at relapse. Given its driving role in disease progression and therapy resistance, Mcl-1 inhibition has emerged as a promising therapeutic target, prompting ongoing research into the development and clinical evaluation of Mcl-1 inhibitors, particularly for patients with refractory or relapsed MM. Here, we show that KS18 is a potent and selective Mcl-1 inhibitor in both sensitive and chemo-resistant MM cells in vitro, and it outperforms other clinically tested Mcl-1 inhibitors such as S63845, VU661013, and AZD5991 in resistant cells. Given the many intracellular interactions of Mcl-1, inhibition can result in signaling changes that can either promote or compensate for the intended apoptotic effect. Our research indicates that KS18 causes a decreased p-ERK ½ expression, a kinase which phosphorylates and stabilizes Mcl-1. However, inhibition of p-ERK ½ via Trametinib, an FDA approved MAPK inhibitor, does not affect Mcl-1. Additionally, KS18 upregulates LC3, a key protein of autophagy, and this is not observed in other Mcl-1 inhibitors. Autophagic induced cell death has been observed in response to chemotherapeutic agents. Cells resistant to Mcl-1 inhibitor S63845 still responded to KS18 and exhibited similar upregulation in LC3. These observations provide valuable insights into effects of potent Mcl-1 inhibition and ways to enhance its apoptotic effects while minimizing chemotoxicity in patients.