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Review
. 2019 Nov 15;25(22):6581-6589.
doi: 10.1158/1078-0432.CCR-19-1089. Epub 2019 Jun 21.

Targeting Topoisomerase I in the Era of Precision Medicine

Anish Thomas  1 , Yves Pommier  1
Affiliations
Review

Targeting Topoisomerase I in the Era of Precision Medicine

Anish Thomas et al. Clin Cancer Res. .

Abstract

Irinotecan and topotecan have been widely used as anticancer drugs for the past 20 years. Because of their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecins are also widely used to elucidate the DNA repair pathways associated with DNA-protein cross-links and replication stress. This review summarizes the basic molecular mechanisms of action of TOP1 inhibitors, their current use, and limitations as anticancer agents. We introduce new therapeutic strategies based on novel TOP1 inhibitor chemical scaffolds including the indenoisoquinolines LMP400 (indotecan), LMP776 (indimitecan), and LMP744, and on tumor-targeted delivery TOP1 inhibitors using liposome, PEGylation, and antibody-drug conjugates. We also address how tumor-specific determinants such as homologous recombination defects (HRD and BRCAness) and Schlafen 11 (SLFN11) expression can be used to guide clinical application of TOP1 inhibitors in combination with DNA damage response inhibitors including PARP, ATR, CHEK1, and ATM inhibitors.

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Conflict of interest statement

Disclosures/conflicts of interest: None

Figures

Figure 1.
Figure 1.
Outline of the molecular pharmacology and response determinants of clinical TOP1 inhibitors. A: Right: Chemical structures of the camptothecin derivatives used in the clinic. R1, R2 and R3 refer to the positions of substitutions that confer water solubility to irinotecan and topotecan. Camptothecins are active in lactone form and are readily inactivated at physiological pH in the blood and tissues by E-ring hydrolysis to their ring-open carboxylate form (top right), which is sequestered by serum albumin. Left: The clinical indenoisoquinoline derivatives, LMP400, LMP776 and LMP744. B: Both the camptothecins and indenoisoquinolines trap TOP1CCs by binding at the enzyme-DNA interface. C: Replication damage induced by TOP1 inhibitors. D. Collision of a replication fork with a TOP1CC on the leading strand for DNA synthesis generates a single-ended DNA double-strand break (DSE: double-stranded end) by replication run-off. E. Alternatively, the colliding fork can be remodeled by replication fork reversal (promoted by HLTF, ZRANB3, SMARCL1, RAD51 and PCNA polyubiquitylation) which remodels the TOP1CC to a potentially reversible configuration. Fork restart is promoted by the helicase RecQ1 and the MCM10 replication helicase. PARylation of RecQ1 prevents its activity and thereby keep forks in the reversed configuration. F. Collisions of transcription and replication with trapped TOP1CCs induce the degradation of TOP1 by the ubiquitin proteasome pathway and engage the chromatin response by phosphorylation of histone H2AX (γH2AX). TOP1CCs are excised by TDP1 (tyrosyl DNA phosphodiesterase) and the endonuclease XPF-ERCC1. The primary cytotoxic lesions in cancer cells result from collisions between the trapped TOP1CCs and replication forks. These collisions are repaired by HDR (homology directed repair) and activating ATR (Ataxia Telangiectasia related) and CHK1 kinases as well as PARP (poly[ADPribose]polymerase). Replication collisions also activate the cell death pathways by engaging p53 (TP53) and Schlafen 11 (SLFN11).
Figure 2.
Figure 2.
Rationale for gap-scheduling combination therapies with tumor-targeted TOP1 inhibitors (TTTi) and DNA damage response inhibitors (DDRi) (such as PARPi, ATRi or ATMi…). The TTTi given on day-1 of each cycle initially produces TOP1cc both in normal and tumor tissues (brown area). After a 2–3-day gap, the TTTi is selectively retained in tumor tissues (green area). Treatment with the DDRi is then initiated (red arrows) while TOP1cc are present in the tumor tissues but not in normal tissues. The DDRi is stopped 1–2 days before the next cycle. Such “gap-schedule” avoids overlapping toxicity for normal tissues.
See this image and copyright information in PMC

References

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