Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers

Kimiyo N. Yamamoto, Kouji Hirota, Shunichi Takeda, Hiroshi Haeno

研究成果: ジャーナルへの寄稿記事

6 引用 (Scopus)

抄録

Platinum drugs and PARP inhibitors ("PARPis") are considered to be effective in BRCA-associated cancers with impaired DNA repair. These agents cause stalled and collapsed replication forks and create double-strand breaks effectively in the absence of repair mechanisms, resulting in arrest of the cell cycle and induction of cell death. However, recent studies have shown failure of these chemotherapeutic agents due to emerging drug resistance. In this study, we developed a stochastic model of BRCA-associated cancer progression in which there are four cancer populations: those with (i) functional BRCA, (ii) dysfunctional BRCA, (iii) functional BRCA and a growth advantage, and (iv) dysfunctional BRCA and a growth advantage. These four cancer populations expand from one cancer cell with normal repair function until the total cell number reaches a detectable amount. We derived formulas for the probability and expected numbers of each population at the time of detection. Furthermore, we extended the model to consider the tumor dynamics during treatment. Results from the model were validated and showed good agreement with clinical and experimental evidence in BRCA-associated cancers. Based on the model, we investigated conditions in which drug resistance during the treatment course originated from either a preexisting drug-resistant population or a de novo population, due to secondary mutations. Finally, we found that platinum drugs and PARPis were effective if (i) BRCA inactivation is present, (ii) the cancer was diagnosed early, and (iii) tumor growth is rapid. Our results indicate that different types of cancers have a preferential way of acquiring resistance to platinum drugs and PARPis according to their growth and mutational characteristics.

元の言語英語
記事番号e105724
ジャーナルPloS one
9
発行部数8
DOI
出版物ステータス出版済み - 8 26 2014

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platinum
Platinum
drugs
neoplasms
Pharmaceutical Preparations
Neoplasms
Repair
Tumors
Cells
drug resistance
Population
Growth
Drug Resistance
inactivation
Cell death
Stochastic models
Poly(ADP-ribose) Polymerase Inhibitors
DNA repair
Cell Cycle Checkpoints
cell death

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

これを引用

Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers. / Yamamoto, Kimiyo N.; Hirota, Kouji; Takeda, Shunichi; Haeno, Hiroshi.

:: PloS one, 巻 9, 番号 8, e105724, 26.08.2014.

研究成果: ジャーナルへの寄稿記事

Yamamoto, Kimiyo N. ; Hirota, Kouji ; Takeda, Shunichi ; Haeno, Hiroshi. / Evolution of pre-existing versus acquired resistance to platinum drugs and PARP inhibitors in BRCA-associated cancers. :: PloS one. 2014 ; 巻 9, 番号 8.
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