Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells
Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton’s tyrosine kinase (BTK)...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.894535/full |
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| author | Weam Othman Elbezanti Weam Othman Elbezanti Omar S. Al-Odat Omar S. Al-Odat Robert Chitren Robert Chitren Jaikee Kumar Singh Sandeep Kumar Srivastava Krishne Gowda Shantu Amin Gavin P. Robertson Venkatesh V. Nemmara Subash C. Jonnalagadda Tulin Budak-Alpdogan Manoj K. Pandey |
| author_facet | Weam Othman Elbezanti Weam Othman Elbezanti Omar S. Al-Odat Omar S. Al-Odat Robert Chitren Robert Chitren Jaikee Kumar Singh Sandeep Kumar Srivastava Krishne Gowda Shantu Amin Gavin P. Robertson Venkatesh V. Nemmara Subash C. Jonnalagadda Tulin Budak-Alpdogan Manoj K. Pandey |
| author_sort | Weam Othman Elbezanti |
| collection | DOAJ |
| description | Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton’s tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents. |
| first_indexed | 2024-04-11T12:05:22Z |
| format | Article |
| id | doaj.art-6aace12e025c4c0bab03f2c7841776cc |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T12:05:22Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-6aace12e025c4c0bab03f2c7841776cc2022-12-22T04:24:44ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-09-011310.3389/fphar.2022.894535894535Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cellsWeam Othman Elbezanti0Weam Othman Elbezanti1Omar S. Al-Odat2Omar S. Al-Odat3Robert Chitren4Robert Chitren5Jaikee Kumar Singh6Sandeep Kumar Srivastava7Krishne Gowda8Shantu Amin9Gavin P. Robertson10Venkatesh V. Nemmara11Subash C. Jonnalagadda12Tulin Budak-Alpdogan13Manoj K. Pandey14Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United StatesDepartment of Hematology, MD Anderson Cancer Center at Cooper, Cooper Health University, Camden, NJ, United StatesDepartment of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United StatesDepartment of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United StatesDepartment of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United StatesDepartment of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United StatesDepartment of Biosciences, Manipal University Jaipur, Jaipur, IndiaDepartment of Biosciences, Manipal University Jaipur, Jaipur, IndiaDepartment of Pharmacology, Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, United StatesDepartment of Pharmacology, Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, United StatesDepartment of Pharmacology, Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, United StatesDepartment of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United StatesDepartment of Chemistry and Biochemistry, College of Science and Mathematics, Rowan University, Glassboro, NJ, United StatesDepartment of Hematology, MD Anderson Cancer Center at Cooper, Cooper Health University, Camden, NJ, United StatesDepartment of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United StatesDespite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton’s tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents.https://www.frontiersin.org/articles/10.3389/fphar.2022.894535/fullBruton’s tyrosine kinaseBtk inhibitormultiple myelomahematological malignanciesmultiple myeloma stem cell-like cellsacquired mutation |
| spellingShingle | Weam Othman Elbezanti Weam Othman Elbezanti Omar S. Al-Odat Omar S. Al-Odat Robert Chitren Robert Chitren Jaikee Kumar Singh Sandeep Kumar Srivastava Krishne Gowda Shantu Amin Gavin P. Robertson Venkatesh V. Nemmara Subash C. Jonnalagadda Tulin Budak-Alpdogan Manoj K. Pandey Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells Frontiers in Pharmacology Bruton’s tyrosine kinase Btk inhibitor multiple myeloma hematological malignancies multiple myeloma stem cell-like cells acquired mutation |
| title | Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells |
| title_full | Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells |
| title_fullStr | Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells |
| title_full_unstemmed | Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells |
| title_short | Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells |
| title_sort | development of a novel bruton s tyrosine kinase inhibitor that exerts anti cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell like cells |
| topic | Bruton’s tyrosine kinase Btk inhibitor multiple myeloma hematological malignancies multiple myeloma stem cell-like cells acquired mutation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.894535/full |
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