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. 2014 Apr 11;19(2):233–242. doi: 10.2478/s11658-014-0191-7

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

Ziwen Wang 1,✉, Yujung Huang 2, Jiqiang Zhang 3,✉
PMCID: PMC6275747  PMID: 24728800

Abstract

Radiotherapy and chemotherapeutic agents that damage DNA are the current major non-surgical means of treating cancer. However, many patients develop resistances to chemotherapy drugs in their later lives. The PI3K and Ras signaling pathways are deregulated in most cancers, so molecularly targeting PI3K-Akt or Ras-MAPK signaling sensitizes many cancer types to radiotherapy and chemotherapy, but the underlying molecular mechanisms have yet to be determined. During the multi-step processes of tumorigenesis, cancer cells gain the capability to disrupt the cell cycle checkpoint and increase the activity of CDK4/6 by disrupting the PI3K, Ras, p53, and Rb signaling circuits. Recent advances have demonstrated that PI3K-Akt-mTOR signaling controls FANCD2 and ribonucleotide reductase (RNR). FANCD2 plays an important role in the resistance of cells to DNA damage agents and the activation of DNA damage checkpoints, while RNR is critical for the completion of DNA replication and repair in response to DNA damage and replication stress. Regulation of FANCD2 and RNR suggests that cancer cells depend on PI3K-Akt-mTOR signaling for survival in response to DNA damage, indicating that the PI3K-AktmTOR pathway promotes resistance to chemotherapy and radiotherapy by enhancing DNA damage repair.

Keywords: PI3K, Akt, Target of rapamycin, Ribonucleotide reductase, p53, FANCD2, Drug resistance, DNA damage response, Chemotherapy, Radiotherapy, ATM

Full Text

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Abbreviations used

AMPK1

AMP-activated protein kinase

ATM kinase

ataxiatelangiectasia mutated kinase

ATR

ataxia telangiectasia and Rad3-related

CDK4/6

cyclin-dependent kinase 4/6

Chk1

checkpoint kinase 1

Chk2

checkpoint kinase 2

FA

Fanconi anemia

FANCD2

Fanconi anemia group D2

FANCI

Fanconi anemia group I

HR

homologous recombination

ICL

DNA interstrand crosslinker

IGFBP-3

insulin-like growth factor binding protein 3

IRS

insulin receptor substrate

MAPK

mitogen-activated protein kinase

mTOR

mammalian target of rapamycin

NER

nucleotide excision repair

PH

pleckstrin homology

PI3K

phosphoinositide 3-kinase

PIP2

phosphatidylinositol 4,5-phosphate

PIP3

phosphatidylinositol 3,4,5-trisphosphate

PTEN

phosphatase/tensin homolog deleted on chromosome 10

Rb

retinoblastoma

Rheb

Ras-homolog enriched in brain

RNR

ribonucleotide reductase

RTK

receptor tyrosine kinase

TLS

translesion DNA synthesis

TSC2

tuberous sclerosis complex-2

Contributor Information

Ziwen Wang, Phone: (86) 9679-9893, Email: wangziwen8080@163.com.

Jiqiang Zhang, Phone: (86)-23-68752223, Email: zhangjqtmmu@yahoo.com.

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