College
College of Science & Mathematics
Keywords
Multiple Myeloma, Drug resistance, Mcl-1 inhibition, Hematological Malignancies
Date of Presentation
5-1-2025 12:00 AM
Poster Abstract
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.
Disciplines
Biochemistry, Biophysics, and Structural Biology | Cancer Biology | Cell Biology | Hemic and Lymphatic Diseases | Medical Biochemistry | Medical Cell Biology | Medicine and Health Sciences | Neoplasms
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Cancer Biology Commons, Cell Biology Commons, Hemic and Lymphatic Diseases Commons, Medical Biochemistry Commons, Medical Cell Biology Commons, Neoplasms Commons
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.
