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. 2021 Apr 1;27(7):1833-1835.
doi: 10.1158/1078-0432.CCR-20-4708. Epub 2021 Jan 20.

Morning for Irofulven, What Could be fiNER?

Haoyang Jiang  1 , Roger A Greenberg  2
Affiliations

Morning for Irofulven, What Could be fiNER?

Haoyang Jiang et al. Clin Cancer Res. .

Abstract

Cancers with DNA repair dysfunction are vulnerable to DNA-damaging agents that invoke a requirement for the disabled repair mechanism. Genome sequencing, coupled with a detailed understanding of mechanisms of DNA repair, has accelerated the discovery of pathway-selective agents that target DNA repair deficiencies in a tumor tissue agnostic manner.See related articles by Topka et al., p. 1997 and Börcsök et al., p. 2011.

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Conflict of interest statement

Conflicts of Interest: R.A.G. is a founder and scientific advisory board member of RADD Pharmaceuticals and JAMM Therapeutics

Figures

Figure.
Figure.. Targeting DNA repair deficiencies in cancer.
Platinum chemotherapy causes intra- and inter-strand DNA crosslinks that are repaired by TC-NER and a combination of FA(Fanconi Anemia) and BRCA dependent HR mechanisms. Irofluven leads to DNA adducts that specifically require repair by TC-NER. ERCC2/3 encodes the DNA helicase XPD and XPB respectively, which are subunits of the TFIIH complex. Their mutations lead to deficient TC-NER and hypersensitivity to Irofluven. PARP inhibitors (PARPi) trap PARP1/2 on DNA, leading to increased repair by BRCA1 and BRCA2 dependent HR. HR deficient cells fail to repair DNA damage caused by PARPi.
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References

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