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

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.

Abbreviations

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

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Correspondence to Ziwen Wang or Jiqiang Zhang.

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Wang, Z., Huang, Y. & Zhang, J. Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy. Cell Mol Biol Lett 19, 233–242 (2014). https://doi.org/10.2478/s11658-014-0191-7

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Keywords

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