Targeting CDK16 Abrogates Growth-Factor Mediated TKI Resistance in AML

• Published in: Blood 2024-11, Vol.144, p.5786-5786
• Main Authors: Kesarwani, Meenu, Kincaid, Zachary, Azhar, Mohammad, Azam, Mohammad
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-211448

Introduction. Mutations in the Fms-like tyrosine kinase 3 (FLT3) gene are among the most common genetic lesions in AML, associated with poor prognosis and high relapse rates. Targeted TKI therapies against FLT3 have shown promise, yet clinical resistance remains a significant challenge. Using phospho and chemiproteomic analyses of FLT3ITD expressing cells revealed CDK16 drive treatment resistance to chemotherapy during growth factor signaling. Targeting CDK16 in combination with FLT3 tyrosine kinase inhibitor (TKI) or BCL2 inhibitor show synergistic response and significantly prolonged the survival of mice harboring AML. Result. Using mouse cell lines expressing FLT3ITD treated with gilteritinib with and without growth factors (growth factor signaling confers resistance to TKI) were subjected to whole genome phosphoproteome and total proteome analyses. This analysis revealed significant changes in abundance and phosphorylation of CDK and MAPK family members in resistant cells. Notably, we noted persistent upregulation of CDK2, CDK 12, CDK13 and CDK20 in TKI resistant cells. Using CRISPR-CAS9 mediated knock-out of these target genes revealed that deletion of CDK12, CDK13 and CDK16 confers strong sensitivity to TKI treatment. Our findings demonstrate that CDK16 inhibition significantly reduces cell viability, induces apoptosis, and impairs clonogenic potential in FLT3-mutated AML cells. Mechanistically, CDK16 inhibition disrupts key signaling pathways that stabilizes P53, highlighting its potential to overcome resistance to FLT3-targeted therapies. Moreover, in vivo studies using xenograft models of FLT3-mutated AML revealed that CDK16 inhibition markedly suppresses tumor growth and enhances overall survival. These results suggest that CDK16 inhibitors could serve as a novel therapeutic strategy for FLT3-mutated AML, either as monotherapy or in combination with existing FLT3 inhibitors. Conclusions. Our research underscores the therapeutic potential of CDK16 inhibition in FLT3-mutated AML, providing a compelling rationale for the clinical evaluation of CDK16 inhibitors in this challenging subset of AML patients. Further studies are warranted to explore the full therapeutic implications and to optimize combination strategies for improved patient outcomes. No relevant conflicts of interest to declare.