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Biomarkers of Response and Resistance to DNA Repair Targeted Therapies Elizabeth H

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Biomarkers of Response and Resistance to DNA Repair Targeted Therapies Elizabeth H Published OnlineFirst September 27, 2016; DOI: 10.1158/1078-0432.CCR-16-0247 Review Clinical Cancer Research Biomarkers of Response and Resistance to DNA Repair Targeted Therapies Elizabeth H. Stover1, Panagiotis A. Konstantinopoulos1, Ursula A. Matulonis1, and Elizabeth M. Swisher2 Abstract Drugs targeting DNA damage repair (DDR) pathways are repair targeted agents currently in clinical trials and the exciting new agents in cancer therapy. Many of these drugs emerging biomarkers of response and resistance to these exhibit synthetic lethality with defects in DNA repair in agents: genetic and genomic analysis of DDR pathways, cancer cells. For example, ovarian cancers with impaired genomic signatures of mutational processes, expression of homologous recombination DNA repair show increased DNA repair proteins, and functional assays for DNA repair sensitivity to poly(ADP-ribose) polymerase (PARP) inhibi- capacity. We review biomarkers that may predict response to tors. Understanding the activity of different DNA repair selected DNA repair targeted agents, including PARP inhibi- pathways in individual tumors, and the correlations between tors, inhibitors of the DNA damage sensors ATM and ATR, DNA repair function and drug response, will be critical to and inhibitors of nonhomologous end joining. Finally, we patient selection for DNA repair targeted agents. Genomic introduce emerging categories of drugs targeting DDR and and functional assays of DNA repair pathway activity are new strategies for integrating DNA repair targeted therapies being investigated as potential biomarkers of response to into clinical practice, including combination regimens. Gen- targeted therapies. Furthermore, alterations in DNA repair erating and validating robust biomarkers will optimize the function generate resistance to DNA repair targeted agents, efficacy of DNA repair targeted therapies and maximize their and DNA repair states may predict intrinsic or acquired drug impact on cancer treatment. Clin Cancer Res; 22(23); 1–10. resistance. In this review, we provide an overview of DNA Ó2016 AACR. Introduction nomas (OC) exhibit dysfunctional HRR (7–10), colon and endo- metrial cancers are enriched in MMR defects (11), bladder cancers Normal and cancer cells rely on multiple DNA damage response have frequent NER mutations (12), and testicular germ cell (DDR) pathways specialized to repair specific forms of DNA tumors may be functionally deficient in NER and other DDR damage (Table 1; refs. 1–4). Key pathways include base excision pathways (13, 14). Many biomarkers for response to DNA repair repair (BER), nucleotide excision repair (NER), mismatch repair targeted therapies reflect specific alterations in DDR pathways or (MMR), homologous recombination repair (HRR), nonhomolo- genomic signatures resulting from aberrant repair. gous end-joining (NHEJ), and interstrand crosslink repair (ICL). If Cytotoxic chemotherapies induce particular forms of DNA canonical repair pathways are deficient, or repair is unsuccessful, damage that trigger specific repair pathways. Therefore, cancers error-prone alternative pathways may be employed (e.g., alt-NHEJ, with DNA repair deficiencies show increased sensitivity to certain single-strand annealing, or translesion synthesis; refs. 1–4). chemotherapeutics. For instance, OC patients with germline DNA repair targeted therapies exploit DNA repair defects in BRCA1 or BRCA2 (BRCA1/2) mutations (HRR deficiency) and cancer cells to generate synthetic lethality (cell death resulting from bladder cancer patients with somatic ERCC2 mutations (NER simultaneous loss or inhibition of two critical functions; for pathway) are more sensitive to platinum agents (15), likely due to example, cancer cells defective in one DNA repair pathway rely decreased capacity to repair platinum-induced DNA damage. on alternate repair pathways; inhibition of a second repair path- HRR and BER deficiencies sensitize cancer cells to topoisomer- way then results in cell death, an effect which selectively targets ase-I inhibitors (e.g., topotecan), whereas HRR and NHEJ defi- repair-deficient cancer cells; refs. 5, 6). DNA repair defects vary by ciencies sensitize to topoisomerase-II inhibitors (e.g., doxorubi- cancer type. For example, approximately 50% of ovarian carci- cin and etoposide; ref. 16). HRR deficiency confers sensitivity to inhibitors of the PARP enzyme, which is vital to several DNA repair pathways, including 1 2 Dana-Farber Cancer Institute, Boston, Massachusetts. University of Washing- BER and NHEJ. Developing biomarkers of DDR function and ton, Seattle, Washington. correlating DNA repair capacity with sensitivity to targeted agents Note: Supplementary data for this article are available at Clinical Cancer is critical to optimizing efficacy of targeted DNA repair drugs. In Research Online (http://clincancerres.aacrjournals.org/). this review, we describe candidate biomarkers of response (and Corresponding Author: Elizabeth M. Swisher, University of Washington, 1959 NE resistance) to DNA repair targeted therapies. Genomic sequencing Pacific Street, Seattle, WA 98195. Phone: 206-543-3669; Fax: 206-543-8315; studies have demonstrated frequent DDR alterations in diverse E-mail: [email protected] cancers, suggesting that DNA repair targeted agents may be doi: 10.1158/1078-0432.CCR-16-0247 broadly active in cancer therapy and highlighting the need for Ó2016 American Association for Cancer Research. accurate biomarkers of response (17, 18). www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 27, 2016; DOI: 10.1158/1078-0432.CCR-16-0247 Stover et al. Table 1. DDR pathways and associated signaling pathways Inhibitors of Mechanism Type of damage Function Key genes pathway proteins DNA damage recognition, signaling, and checkpoints DNA double-strand – Double-strand breaks (DSB) – Recognition of DNA damage and MRN complex: MRE11, PARP inhibitors break recognition recruitment of repair machinery RAD50, NBN (NBS1) MRE11 inhibitors RBBP8 (CTIP) (e.g., mirin) PARP1 DNA repair Various – Coordination of cell cycle with DNA repair ATM ATM inhibitors checkpoints – Induction of cell death for irreparable ATR ATR inhibitors lesions CHEK1 (Chk1) Chk1/2 inhibitors CHEK2 (Chk2) Wee1 inhibitors TP53 (p53) H2AFX (Histone H2A.X) Cell-cycle Various – Regulate cell cycle to allow time for DNA Genes encoding cyclin/ CDK inhibitors checkpoints repair activities and coordinate repair CDK proteins with progression through cell cycle Replication stress – Slowing/stalling of replicative DNA – Stabilization of stalled replication forks and RPA1, RPA2 ATR inhibitors response polymerase progression due to a DNA repair to enable replication restart. ATR Chk1 inhibitors variety of cellular stresses, resulting in If this fails, DNA damage (e.g., DSBs) ATRIP stalled replication forks. can result. CHEK1 (Chk1) TOPBP1 DNA repair pathways Direct repair – Base modifications, including – Direct repair of modified bases by MGMT MGMT inhibitors O6-methylguanine, 1-methyladenine, enzymatic processes: demethylation ALKBH1 3-methylcytosine, and N-methylated adenosine and cytosine – Examples: alkylating agents Base excision repair – Damaged and modified bases – Excision of damaged base to generate a OGG1 APE-1 inhibitors (BER) – Single-strand breaks basic site, followed by nicking, resynthesis, NEIL1, NEIL2, NEIL3 PARP inhibitors – Short patch repair – Examples: radiotherapy, and single-strand break repair (SSBR) APEX1 PNKP inhibitors – Long patch repair alkylating agents PARP1, PARP2 POLB inhibitors – Single-strand XRCC1 break repair POLB LIG1 LIG3 FEN1 PNKP MUTYH Nucleotide excision – Bulky DNA adducts – Damage recognition and unwinding of RAD23B repair (NER) – Inter- and intrastrand crosslinks local DNA, nuclease excision, DDB1 – Transcription- – Examples: platinum agents, resynthesis, and SSBR RPA1, RPA2 coupled NER ultraviolet (UV) light ERCC1, ERCC2 (XPD), – Global NER ERCC3, ERCC5, ERCC6, ERCC8 GTF2H1, GTF2H2, GTF2H4, GTF2H5, GTF2F2 CDK7 MMS19 MNAT1 XPA, XPC CCNH PCNA RFC1 Mismatch repair – Base mismatches (single nucleotide – Recognition and removal of mismatched MLH1 (MMR) mutations and small insertions/ base followed by resynthesis of correct MLH3 deletions) base and SSBR MSH2 – Examples: alkylating agents, MSH6 replication errors PMS2 Homologous – Double-strand breaks – Unwinding and resection at DSB to BRCA1 RAD51/2 recombination – Examples: radiation, topoisomerase generate single-strand end, strand BRCA2 inhibitors repair (HRR) inhibitors, cisplatin invasion, homologous recombination with RAD51, RAD52 BLM inhibitors sister chromatid, resynthesis, and TP53BP1 resolution. Results in exact repair using RBBP8 (CTIP) sequences from sister chromatid. EXO1 RPA1, RPA2 BLM PALB2 MRN complex: MRE11, RAD50, NBN (NBS1) (Continued on the following page) OF2 Clin Cancer Res; 22(23) December 1, 2016 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 27, 2016; DOI: 10.1158/1078-0432.CCR-16-0247 Biomarkers of DNA Repair Targeted Therapies Table 1. DDR pathways and associated signaling pathways (Cont'd ) Inhibitors of Mechanism Type of damage Function Key genes pathway proteins Interstrand crosslink – Interstrand crosslinks – Crosslinks are excised and then repaired BRCA2 repair (ICL) – Examples: platinum agents, nitrogen by HRR (or other mechanisms) FANCA mustards, mitomycin
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