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Targeting a CDH1-TK1-dependent DNA Synthesis Pathway Overcomes Chemoresistance in Acute Myeloid Leukemia
Xiaomin Feng1,2, Li Huo3, Clifford Pang1,4
1Clinical Research Centre, Guangdong Clifford Hospital, Guangzhou, China.
Hematological Oncology
|August 8, 2026
Summary
Thymidine kinase 1 (TK1) drives chemotherapy resistance in acute myeloid leukemia (AML) by enabling leukemic cells to tolerate replication stress. Targeting TK1 can restore drug sensitivity and improve outcomes in relapsed/refractory AML.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Relapsed and refractory acute myeloid leukemia (AML) presents significant treatment challenges.
- Leukemic cells develop resistance to chemotherapy, partly through adaptation to replication stress induced by nucleoside analogues.
Purpose of the Study:
- To identify key molecular mechanisms underlying chemotherapy resistance in AML.
- To investigate the role of thymidine kinase 1 (TK1) in chemoresistance and explore therapeutic strategies targeting this pathway.
Main Methods:
- Integrated analysis of transcriptomic data from TCGA, Beat AML, and murine AML models.
- Genetic manipulation of TK1 and APC/C-CDH1 activity in AML cells.
- In vivo studies using patient-derived xenograft models of relapsed/refractory AML.
- Combination therapy involving topoisomerase I and WEE1 inhibitors.
Main Results:
- High TK1 expression correlates with poor prognosis, cytarabine resistance, and nucleotide salvage pathways in AML.
- TK1 upregulation in Mll-Af9/Setd2-mutant AML cells reduces de novo nucleotide synthesis and confers resistance to daunorubicin plus cytarabine.
- Genetic suppression of TK1 restores chemosensitivity by increasing DNA damage.
- Impaired APC/C-CDH1 activity leads to TK1 accumulation, enhancing replication stress tolerance and drug resistance.
Conclusions:
- A CDH1-TK1 pathway promotes salvage-dependent replication stress tolerance in AML.
- TK1 is a potential biomarker for identifying patients who may benefit from replication stress-targeted therapies.
- Combination therapy of topoisomerase I and WEE1 inhibitors shows promise in reducing leukemic burden and improving survival in TK1-high AML.
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