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Loss-of-function shRNA screens to identify mechanisms of PARP inhibitor resistance in BRCA1-mutated mouse mammary tumors
Xu, G.
2016
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citation for published version (APA)
Xu, G. (2016). Loss-of-function shRNA screens to identify mechanisms of PARP inhibitor resistance in BRCA1-mutated mouse mammary tumors.
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11
CHAPTER 1
GENERAL INTRODUCTION
PARP inhibitor resistance - what is beyond
BRCA1 or BRCA2 restoration?
Guotai Xu, Jos Jonkers, Sven Rottenberg
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Abstract
Nearly 10 years ago the usefulness of poly(ADP-ribose) polymerase (PARP) inhibitors to kill BRCA1 or BRCA2-deficient cells was reported, and this finding has served as a prime example of the concept of synthetic lethality in the context of anticancer therapy. The clinical translation of this finding has undergone several ups and downs, however. Despite spectacular responses seen in some patients with BRCA-deficient breast or ovarian cancers, other patients did not show the expected benefit from PARP inhibitor therapy. Thus, like for all novel tailored anti-cancer drugs, upfront and secondary resistance remain major hurdles in the implementation of the initial preclinical finding. We know at least one clinically relevant mechanism of PARP inhibitor resistance: the reversion of BRCA function by secondary mutations. Nevertheless, it is also clear that this mechanism does not explain all cases of resistance. At the moment, we only have a poor understanding of BRCA reversion-independent resistance mechanisms. Preclinical data have pointed in several directions, e.g. increased drug efflux, reduced drug target levels, or alternative DNA repair. Here, we discuss these mechanisms with a focus on potential DNA repair adaptations.
Keywords
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Text
1. A defect in homology-directed DNA repair as a target for anti-cancer therapy
14
repair by the HRR pathway is impaired in a substantial fraction of breast and ovarian cancers.
In addition, HRR deficiencies (HRD) can be associated with other cancer types. BRCA1/2 mutation carriers have an increased risk to develop prostate, pancreatic, bile duct, and stomach cancer (Breast Cancer Linkage Consortium, 1999; Thompson et al., 2002). Alterations of other genes that encode for proteins involved in the HRR pathway such as PALB2 and RAD54B were identified in colon cancer and lymphomas. Recently, an HRD signature based on the differential expression of 230 genes in isogenic HRR-proficient versus – deficient cells was reported (Peng et al., 2014). Intriguingly, in addition to breast and ovarian cancers this signature also identifies lung cancer patients who may have a therapy benefit. Thus, in addition to breast and ovarian cancers, other cancer types may also be eligible to HRD-targeting therapy (Evers et al., 2010).
In the clinic, DNA damage is frequently induced by topoisomerase I or II inhibitors like topotecan and doxorubicin, or by DNA cross-linking and alkylating agents like platinum-based drugs or cyclophosphamide. High sensitivity of BRCA1/2-related breast cancers to DNA-damaging agents was confirmed by several retrospective clinical studies (Chappuis et al., 2002; Lips et al., 2011; Silver et al., 2010). Although these therapies may be beneficial, they usually do not cure patients and they also generate significant toxicities in normal tissues (Kelland, 2007).
15 they reflect the various processes PARP1 is involved in (De Lorenzo et al., 2013):
1.1. Trapping of PARP1 at sites of DNA damage
Nicked DNA is sensed by the N-terminal zinc fingers of PARP1 resulting in increased PAR formation (Benjamin and Gill, 1980; de Murcia and Ménissier de Murcia, 1994; Langelier and Pascal, 2013). In addition to PARylation of a wide range of substrates, PAR is covalently bound to PARP1 itself (D’Amours et al., 1999). The resulting increased negative charge then dissociates PARylated PARP1 from the DNA (Satoh and Lindahl, 1992). In their study Satoh and Lindahl (1992) already showed that catalytically inactive PARP1 (due to lack of
NAD+) still inhibits DNA repair. Recently, it was demonstrated that inhibition of
the catalytic domain of PARP1 using small molecule inhibitors increases chromatin-bound PARP, resulting in DNA repair inhibition and increased cytotoxicity to the DNA methylating agent methylmethane sulfate (MMS) (Murai et al., 2012). This confirmed the PARP1 trapping model that was also proposed by others (Helleday, 2011; Kedar et al., 2012; Ström et al., 2011). This model is consistent with studies investigating the combinatorial effect of topoisomerase I
inhibition (Patel et al., 2012b): PARPi treatment of PARP1-/- cells reconstituted
with catalytically inactive PARP1 mutants sensitized cells to the same extend to
topoisomerase I inhibitors as PARP+/+ cells treated with PARPi.
Nevertheless, it is difficult to understand how this poisoning model can account for the synthetic lethality between HRR deficiency and PARP inhibition. PARP1 downregulation has been demonstrated to selectively kill BRCA1/2-deficient cells (Bryant et al., 2005; Farmer et al., 2005; Patel et al., 2011), suggesting that the decreased PAR production is causing cytotoxicity in this context. Still, BRCA defective cells appear to be more sensitive to PARP inhibitors than to PARP depletion by siRNAs (Bryant et al., 2005; Farmer et al., 2005). This leaves the possibility open that PARP1 trapping contributes to the cytotoxicity in HRR-deficient cells.
16
PARP1 activity has been linked to the repair of SSB by the BER pathway (Dantzer et al., 1999; De Vos et al., 2012). Although there may be no immediate role for PARP1 in BER, PARP1 trapping on the SSB intermediate formed during base excision will delay BER-mediated repair of SSBs (Ström et al., 2011). Thus, the synthetic lethality of PARP inhibition and HRR deficiency was explained by reduced BER activity (Helleday, 2011; Iglehart and Silver, 2009; Yap et al., 2011). Persistent SSBs are converted into double-strand breaks (DSB) during replication or as a consequence of interactions with transcription complexes. Whereas HRR-proficient normal cells of the body can repair the DSBs in an error-free manner, HRR-deficient tumor cells (due to BRCA1/2 deficiency) cannot and die.
It has been difficult to experimentally prove the increase in SSBs after PARP inhibition (Helleday, 2011), which would provide support for this model. Moreover, one would expect the same synthetic lethality when another BER component such as XRCC1 is inactivated in HRR-deficient cells. However, experiments using BRCA2-mutant ovarian cancer cells showed that inhibition of XRCC1, in contrast to PARP1, was not cytotoxic (Patel et al., 2011). These results suggest an additional role for PARP1 that is distinct from SSB repair.
1.3. Defective recruitment of BRCA1 to sites of DNA damage
Recently, Li and Yu (2013) reported the interaction between PAR and the BRCA1-binding partner BARD1 as a crucial step for the early recruitment of BRCA1 to sites of DNA damage. BARD1 is well known to interact with the BRCA1 RING domain. As the authors point out, this model obviously fails to clarify the cytotoxicity in cells that completely lack BRCA1. It also does not explain the synthetic lethality with components downstream in the HRR pathway, such as BRCA2 and RAD51.
1.4. Activation of error-prone non-homologous end-joining (NHEJ)
17 Ku80 classical end-joining appears to be inhibited (Hochegger et al., 2006; Paddock et al., 2011; Wang et al., 2006). Further studies suggested an important role for NHEJ activation in PARP inhibition-induced cytotoxicity. For example PARPi-treated HRR-deficient cells show an increase in DNA-PKcs activation and there is a selective increase in chromosomal rearrangements and mutations (Farmer et al., 2005; Patel et al., 2011). Consistent with this notion, inhibition of NHEJ activity due to DNA-PKcs or 53BP1 deficiency diminishes the effect of PARP inhibition (Bunting et al., 2010; Jaspers et al., 2013; Murai et al., 2011; Patel et al., 2011; Williamson et al., 2012). Thus, HRR-deficient cells rely more on NHEJ upon PARP inhibition. The subsequent errors then induce the synthetic lethality.
This model of NHEJ-mediated PARPi cytotoxicity also leaves some open questions: How is the NHEJ pathway activated? Which components of the NHEJ pathway are necessary to induce PARPi-induced killing? How do cells that are deficient in both HRR and NHEJ survive PARP inhibition?
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dead PARP1 mutants are therefore a useful addition, and with the advent of the CRISPR-Cas9 technology their generation is greatly simplified.
2. Drug resistance remains a major hurdle despite the availability of novel anti-cancer drugs
Major efforts of academia and the pharmaceutical industry have gone into the discovery and development of tailored therapies targeting growth-supporting pathways, angiogenesis, cell cycle checkpoints, protein turnover, anti-apoptotic regulation, or DNA repair of various cancers. The hope is that the right (combination of) drugs in the right patient will enable maximal control of tumor growth, similar to an HIV infection, and transform cancer from a deadly disease into a chronic one (Bock and Lengauer, 2012). These efforts have yielded spectacular responses in some cancer patients, e.g. BRAF inhibition in melanoma, EGFR inhibition in non-small cell lung cancers, or HER2-targeting antibodies in breast cancer. Consistent with the preclinical data, the PARPi olaparib also showed substantial single agent activity in patients with BRCA1/2-mutant breast or ovarian cancer (Audeh et al., 2010; Fong et al., 2010, 2009; Gelmon et al., 2011; Tutt et al., 2010). Despite these successes, patients suffering from disseminated cancer who are treated with these therapies are usually not cured, and eventually die from therapy resistance. The clinical experience from these novel anti-cancer drugs exemplifies three common handicaps, similar to those found in classical chemotherapy:
2.1. Some patients do not benefit from the therapy, but do suffer from
19 PARPi are essential to solve this dilemma, and we still lack markers that have been proven in prospective trials to be valid.
2.2. Those patients with metastatic tumors that do respond well are
usually not cured by systemic treatment alone.
2.3. From the residual disease pan-resistant tumors eventually arise
that do not respond to any drug (Borst, 2012).
Unfortunately, our understanding of the mechanisms that underlie such drug resistance is still insufficient to effectively improve available treatments (Lord and Ashworth, 2013). Several mechanisms have been suggested to cause PARPi resistance.
3. PARP inhibitors do not reach their target
A trivial explanation of PARPi resistance would be that the inhibitor does not reach the nucleus of the tumor cells to block PARP1. Not much is known about how the various PARPis enter tumor cells. Using BODIPY-labeled olaparib rapid uptake and in vivo target inhibition of tumor cells was demonstrated at subcellular resolution (Dubach et al., 2014; Thurber et al., 2013). This is consistent with earlier observations in mouse and human tumors that show rapid uptake and accumulation of olaparib (Fong et al., 2009; Rottenberg et al., 2008). In a glioblastoma model insufficient concentrations of veliparib were measured to re-sensitize temozolomide-resistant tumors (Gupta et al., 2014). The fact that veliparib is affected by the drug efflux pumps ABCB1 and ABCG2 at the blood-brain-brain barrier may contribute to this (Lin et al., 2014). Olaparib was also identified as a substrate of ABCB1 (Lawlor et al., 2014; Oplustilova et al., 2012; Rottenberg et al., 2008), and increased expression of the mouse Abcb1a/b genes was observed in olaparib-resistant
Brca1-/-;p53-/- mouse mammary tumors (Rottenberg et al., 2008). We confirmed
that ABCB1-mediated drug efflux is causing olaparib resistance by chemical and genetic inhibition of ABCB1 function (Jaspers et al., 2013; Rottenberg et al., 2008). Increased Abcb1a/b and Abcg2 gene expression was also observed in
Brca2-/-;p53-/- mouse mammary tumors that have undergone
20
tumors can be re-sensitized by the use of the ABCB1 inhibitor tariquidar, the EMT-associated increase of Abcb1a/b gene expression seems to contribute to drug resistance. Intriguingly, increased expression of ABCB1 and multidrug
resistance was observed in Parp1-/- mouse embryonic fibroblasts (Wurzer et al.,
2000). It remains to be determined, however, whether PARP inhibition in general modulates ABCB1 expression.
Despite such preclinical findings, the relevance of ABCB1-mediated drug resistance for human tumors remains controversial (Borst, 2012). Effective inhibitors of P-gp have shown only limited benefit in clinical trials (Amiri-Kordestani et al., 2012). In contrast to the murine Abcb1a/b genes, induction of the human ABCB1 appears to require more complex DNA re-arrangements to overcome promoter methylation (Huff et al., 2006). Using three patient-derived breast cancer xenotransplantation lines with BRCA1 deficiencies, no such re-arrangement was observed in tumors with secondary olaparib resistance (ter Brugge et al., unpublished). Although we anticipate that ABCB1-mediated drug efflux may still be identified as resistance mechanism in some individuals, the major clinical relevance for drug efflux transporters in PARP inhibitor resistance may be more at the level of the blood-brain-barrier. Primary or metastatic HRR-deficient tumors in the brain may not receive the necessary PARPi concentrations due to the activity of ABCB1 and ABCG2. In this context it would be interesting to study the efficacy of the PARPi AZD2461 on brain tumors, as AZD2461 is a poor substrate of ABCB1 (Jaspers et al., 2013).
4. BRCA1/2 alterations
21 Since BRCA1 is also silenced by gene promoter methylation in some patients with sporadic breast or ovarian cancers (Esteller et al., 2000; Rice et al., 2000), it can be anticipated that reversion of promoter methylation causes drug resistance in some cases. In contrast to platinum resistance in ovarian cancers, our knowledge on the frequency of BRCA1/2 functional restoration as a cause of PARPi resistance is limited, however. Genetic reversions have been identified in two patients who were treated with olaparib (Barber et al., 2013), but this mechanism could not explain olaparib resistance in six other patients with BRCA1/2-associated cancers (Ang et al., 2013). Thus, PARPi resistance mechanisms that are independent of BRCA1/2 restoration are clinically relevant. To identify them, genetically engineered mouse models with large intragenic deletions of BRCA1 or BRCA2 are helpful (Jonkers et al., 2001; Liu et al., 2007). In these, no restoration of BRCA1/2 can be achieved to cause therapy
resistance. Intriguingly, all tested Brca1-/-;p53-/-;Abcb1a/b-/- mouse mammary
tumors, which cannot employ BRCA1 restoration or ABCB1-mediated drug efflux, still develop secondary olaparib resistance (Jaspers et al., 2013).
22
DSBs and inactivating mutations in the BRCT domain therefore result in higher PARPi sensitivity. Of note, it was recently shown that although BRCT domain mutant proteins cannot promote DNA end resection, they can still contribute to RAD51 loading and HRR if stabilized by HSP90 (Johnson et al., 2013). This has been suggested to cause PARPi and cisplatin resistance, but the resistant cells have also acquired a 53BP1 mutation resulting in substantially lower 53BP1 protein levels.
5. Reduced PARP1 levels
Consistent with the poisoning model, PARP1 is a major hit in a functional screen for olaparib resistance in haploid ES cells (Pettitt et al., 2013). We also identified PARP1 mutations in an insertional mutagenesis screen for olaparib resistance using haploid KBM7 cells (Guyader et al., unpublished). Nevertheless, these cells are HRR-proficient and substantial olaparib
concentrations (4 μM or 14 μM) were required to select resistant cells. What
about HRR-deficient cells in which lack of PARP1 should be rather toxic? In a shRNA screen (1978 hairpins targeting 381 genes associated with DDR) using
500 nM of olaparib in Brca1-/-;p53-/- mouse mammary tumor cells, there was no
enrichment of any of 5 Parp1-targeting hairpins; in contrast to the obvious enrichment of 53bp1-targeting shRNAs (Xu et al., unpublished). Parp1-targeting shRNAs were also not enriched in a screen using PARPi-treated mouse embryonic stem cells that lack Brca1 (Bouwman et al. unpublished). Reduced
PARP1 protein levels do occur in some Brca1-/-;p53-/-;Abcb1a/b-/- or Brca2-/-;p53
-/-
mouse mammary tumors, but it remains to be determined whether they explain stable olaparib resistance of proliferating tumors (Xu et al., unpublished). Lowered PARP1 levels probably reduce proliferation of BRCA1/2-deficient cells and slowly cycling cells will be less drug sensitive. But as soon as these cells pick up growth, higher PARP1 levels should re-sensitize them to PARPi. It is therefore doubtful whether an analogy to the inhibition of topoisomerase 1 using
topotecan can be expected. In several of the topotecan-resistant Brca1-/-;p53
23 downregulation that does not affect growth, but that is sufficient to cause a small survival benefit. We know from previous experiments of ABCB1-mediated resistance that such a moderate difference in expression is sufficient to cause resistance in vivo (Pajic et al., 2009).
6. Alternative DNA repair mechanisms
Using genomic tools such as large-scale deep sequencing, comparative genomic hybridization and microarray expression analysis, we and others found that inter- and intratumoral heterogeneity severely complicates the discovery of causal relationships between cancer genotype and phenotype in mouse and human tumors (Gerlinger et al., 2012; Jaspers et al., 2013; Rottenberg et al., 2012). The data are mostly correlative, and it is unclear which genetic alterations drive resistance and which are just “passengers”. To tackle this challenge, the use of functional genomic screens in cell lines allows the unbiased identification of genes that play a causal role in modulating therapy responses (Berns and Bernards, 2012). In the absence of sufficient clinical material from PARPi trials, results from these screens can be compared to PARPi resistant tumors in animal models (Figure 1). Since PARPi’s specifically target HRR-deficient cells, such screens have proven ability to identify mechanisms of HRR restoration due to the mutation of another gene (`synthetic viability`). Given the importance of BRCA1 for HRR it came as a surprise that its absence can indeed be alleviated by the deletion of another gene: depletion of 53BP1, which has been shown to be involved in NHEJ, rescues BRCA1-deficient cells (Bouwman et al., 2010; Bunting et al., 2010). Loss of 53BP1 causes synthetic viability in the presence of PARPi in vitro (Bunting et al., 2010), and protein-truncating 53BP1 mutations were identified in a fraction of mouse mammary tumors with acquired PARPi resistance (Jaspers et al., 2013). Cisplatin resistance was also observed in 53BP1- and BRCA1-deficient mouse ES cells (Bouwman et al., 2010). Although tumors relapse earlier, the loss of
53BP1 in Brca1-/-;p53-/- mouse mammary tumors is not sufficient to cause
24
explained by the function of BRCA1 in the repair of crosslinks, which does not appear to be relieved by loss of 53BP1 (Bunting et al., 2012). In contrast to resistance to DNA crosslinking agents, however, loss of 53BP1 may be sufficient to cause PARPi resistance. It remains to be seen whether this mechanism can be confirmed in patients.
Essential factors recruited by phosphorylated 53BP1 to promote NHEJ and to block HRR are RIF1 (Chapman et al., 2013; Di Virgilio et al., 2013; Escribano-Díaz et al., 2013; Feng et al., 2013) and PTIP (Callen et al., 2013). PTIP loss rescues HRR in BRCA1-deficient cells and is largely dispensable for NHEJ during class switch recombination, whereas loss of RIF1 only partially rescues HRR and hypersensitivity produced by PARPi treatment of BRCA1-deficient cells.
Recently, we identified another synthetic viable interaction between PARPi and loss of a DNA repair protein in BRCA1-deficient cells: loss of REV7 (also known as MAD2L2) re-establishes CtIP-dependent end resection of double-strand DNA breaks in BRCA1-deficient cells (Xu et al., manuscript submitted). This results in the restoration of homology-directed repair and causes PARP inhibitor resistance. Like 53BP1, REV7 seems to play a role in DNA end-joining and it counteracts end resection. In addition to its contribution to metaphase-to-anaphase transition (Listovsky and Sale, 2013), REV7 is
well-known to form the TLS polymerase ζ together with the catalytic subunit REV3,
and it interacts with REV1 (Gan et al., 2008). It is possible, however, that the effect of REV7 on DNA end resection is independent of REV1 and REV3. Since the absence of REV7 occurs frequently in triple-negative breast cancer, this might predict a poor response to PARPi therapy in patients with BRCA1-like cancers.
25 there are additional mechanisms that restore homology-directed DNA repair in BRCA1-deficient cells.
It will be of interest to study whether RAD51 foci formation can also be restored in BRCA2-deficient cells. The polymerization of RAD51 at damage sites is regulated by a number of accessory factors (called RAD51 mediators), including the five RAD51 paralogs, SWS1, RAD52, RAD54, SFR1, BRCA1, BRCA2, and PALB2 (Jensen et al., 2013; Qing et al., 2011). Recently, additional factors such as the PCSS complex (Sasanuma et al., 2013) or the MCM8-MCM9 complex (Park et al., 2013) have been identified to assemble RAD51 foci. In this context it is of interest that BRCA2 functions as RAD51 mediator only in taxa beyond yeast. In budding yeast Rad52 interacts directly with both RPA and Rad51 to enable Rad51 to gain access to the site of DNA damage. When put under strong selection pressure, mammalian cancer cells may also find ways to employ BRCA2-independent restoration of RAD51 filament assembly. Still, given the crucial epistatic role for BRCA2 in RAD51 loading in mammalian cells, this would be rather unexpected. Instead, alterations of SSB repair may cause resistance in BRCA2-deficient cells. Since reduced BER was suggested to be crucial for PARPi-induced toxicity, one would expect compensatory SSB repair to show up. Thus far such a mechanism was not identified, however. It may be easier for cells to just decrease PARP1 levels moderately without affecting proliferation and thereby reduce PARP1 trapping-induced toxicity. It will therefore be important to carefully investigate which DDR
alterations contribute to resistance. Brca2-/-;p53-/- mouse mammary tumors in
which no complete restoration of BRCA2 function is possible and in which no increased Abcb1a/b expression is found may be particularly suitable to investigate this.
Changes in cell signaling cascades may also impact on DNA repair and
cause resistance. In olaparib-resistant HCC1937 cells increased
26
phosphorylation can be inhibited by mTORC1 inhibitors, a combination of PARPi’s with rapamycin (derivates) may be a promising combination. These data are consistent with previous reports showing that the PTEN-PI3K pathway contributes to DSB repair (Shen et al., 2007), and that PI3K inhibitors also increase the efficacy of PARPi’s (Juvekar et al., 2012). Moreover, activation of the PI3K/mTOR pathway was associated with poor PARPi response (Cardnell et al., 2013). In contrast, these data are difficult to match with the finding of Mendes-Pereira et al. (2009), suggesting that there is a synthetic lethal interaction between PTEN loss and PARP inhibition. This shows that the precise nature of the interaction between cell signaling and DNA repair still remains to be determined.
7. Outlook
27 preclinical cancer models with defined BRCA2 mutations should help to indicate which type of DDR adaptation can be expected in patients.
Acknowledgements
We wish to thank Piet Borst, Peter Bouwman and Ewa Gogola for critical reading of the manuscript. Nora Gerhards helped with the design of Figure 1. Our work on PARPi resistance is supported by grants from the Netherlands Organization for Scientific Research (NWO-VIDI-91711302 to S. Rottenberg; NWO-VICI 91814643 to J. Jonkers), and the Dutch Cancer Society (KWF projects NKI 2009-4303, NKI 2011-5197 and NKI 2011-5220).
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Figure legend
Figure 1. The use of cohesive model systems to study PARPi resistance. A,
