Targeting of PI3K/AKT signaling and DNA damage response in acute myeloid leukemia: a novel therapeutic strategy to boost chemotherapy response and overcome resistance

Montserrat Estruch; Camilla Vittori; Teresa Muñoz Montesinos; Kristian Reckzeh; Kim Theilgaard-Mönch

doi:10.20517/cdr.2021.76

Targeting of PI3K/AKT signaling and DNA damage response in acute myeloid leukemia: a novel therapeutic strategy to boost chemotherapy response and overcome resistance

Cancer Drug Resist. 2021 Nov 10;4(4):984-995. doi: 10.20517/cdr.2021.76. eCollection 2021.

Authors

Montserrat Estruch^{1

2

3}, Camilla Vittori^{1

2

3}, Teresa Muñoz Montesinos^{1

2

3}, Kristian Reckzeh^{1

2

4}, Kim Theilgaard-Mönch^{1

2

4

5}

Affiliations

¹ The Finsen Laboratory, Rigshospitalet/National University Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
² Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
³ Authors contributed equally.
⁴ Novo Nordisk Foundation Centre for Stem Cell Biology, DanStem, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
⁵ Department of Hematology, Rigshospitalet/National University Hospital, University of Copenhagen, Copenhagen DK-2200, Denmark.

Abstract

Resistance of cancer patients to DNA damaging radiation therapy and chemotherapy remains a major problem in the clinic. The current review discusses the molecular mechanisms of therapy resistance in acute myeloid leukemia (AML) conferred by cooperative chemotherapy-induced DNA damage response (DDR) and mutational activation of PI3K/AKT signaling. In addition, strategies to overcome resistance are discussed, with particular focus on studies underpinning the vast potential of therapies combining standard chemotherapy AML regimens with small molecule inhibitors targeting key regulatory hubs at the interface of DDR and oncogenic signaling pathways.

Keywords: AML; DNA damage response; PI3K/AKT; chemotherapy; resistance.

Publication types

Review