Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia

by Selleckchem | Oct 09 2023

Chemotherapy-resistant acute myeloid leukemia (AML), frequently driven by clonal evolution, has a dismal prognosis. A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockouts involving AraC metabolism and genes that regulate cell cycle arrest (cyclin dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2) and TP53) as contributing to resistance. In human AML cohorts, reduced expression of CDKN2A conferred inferior overall survival and CDKN2A downregulation occurred at relapse in paired diagnosis-relapse samples, validating its clinical relevance. Therapeutically targeting the G1S cell cycle restriction point (with CDK4/6 inhibitor, palbociclib and KAT6A inhibitor, WM-1119, to upregulate CDKN2A) synergized with chemotherapy. Additionally, direct promotion of apoptosis with venetoclax, showed substantial synergy with chemotherapy, overcoming resistance mediated by impaired cell cycle arrest. Altogether, we identify defective cell cycle arrest as a clinically relevant contributor to chemoresistance and identify rationally designed therapeutic combinations that enhance response in AML, potentially circumventing chemoresistance.

Comments:

Your statement highlights the challenges posed by chemotherapy-resistant acute myeloid leukemia (AML) and the potential strategies to overcome this resistance. Research has shown that clonal evolution plays a significant role in chemotherapy resistance in AML. To investigate the mechanisms underlying this resistance, a genome-wide CRISPR knockout screen was conducted using human AML cell lines treated with doxorubicin and cytarabine (Dox/AraC).

The study identified gene knockouts related to AraC metabolism and genes involved in cell cycle arrest, including cyclin-dependent kinase inhibitor 2A (CDKN2A), checkpoint kinase 2 (CHEK2), and TP53, which contributed to chemotherapy resistance. The reduced expression of CDKN2A was associated with inferior overall survival in human AML cohorts. Furthermore, CDKN2A downregulation was observed in paired diagnosis-relapse samples, validating its clinical relevance in AML.

To address the resistance mediated by defective cell cycle arrest, the study explored therapeutic approaches targeting the G1S cell cycle restriction point. The use of a CDK4/6 inhibitor called palbociclib and a KAT6A inhibitor named WM-1119 to upregulate CDKN2A showed synergy with chemotherapy, suggesting that this combination could enhance treatment response in AML.

Another promising strategy mentioned is the direct promotion of apoptosis using venetoclax. This approach demonstrated substantial synergy with chemotherapy, effectively overcoming resistance mediated by impaired cell cycle arrest.

In summary, the study identifies defective cell cycle arrest as a clinically relevant factor contributing to chemoresistance in AML. It also proposes rationally designed therapeutic combinations, such as the use of CDK4/6 inhibitors and KAT6A inhibitors, as well as venetoclax, to enhance the response to chemotherapy in AML and potentially overcome chemoresistance.