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Overcoming Treatment Toxicity through Sequential Therapy

2019; Cell Press; Volume: 35; Issue: 6 Linguagem: Inglês

10.1016/j.ccell.2019.05.006

1878-3686

Jan Benada, Bent Ejlertsen, Claus Storgaard Sørensen,

Cell death mechanisms and regulation

Combined inhibitions of PARP and DNA damage checkpoint have the potential for high anti-cancer efficacy, but concurrent inhibitions have been hampered by intolerable side effects. In this issue of Cancer Cell, Fang and colleagues (Fang et al., 2019Fang Y. McGrail D.J. Sun C. Labrie M. Chen X. Zhang D. Ju Z. Vellano C.P. Lu Y. Li Y. et al.Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy.Cancer Cell. 2019; 35 (this issue): 851-867Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar) propose that sequential inhibitions of PARP and DNA damage checkpoint considerably widen the therapeutic window. Combined inhibitions of PARP and DNA damage checkpoint have the potential for high anti-cancer efficacy, but concurrent inhibitions have been hampered by intolerable side effects. In this issue of Cancer Cell, Fang and colleagues (Fang et al., 2019Fang Y. McGrail D.J. Sun C. Labrie M. Chen X. Zhang D. Ju Z. Vellano C.P. Lu Y. Li Y. et al.Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy.Cancer Cell. 2019; 35 (this issue): 851-867Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar) propose that sequential inhibitions of PARP and DNA damage checkpoint considerably widen the therapeutic window. Specific targeting of cancer cell genome maintenance and DNA damage response (DDR) pathways represent an emerging therapeutic approach in cancer treatment. Currently, a promising class of DDR-targeting drugs is the PARP inhibitors (PARPi). PARP1 and PARP2 act as initial DNA damage sensors and bind to DNA single-strand and double-strand breaks. Upon its binding, PARP is activated and in turn modifies itself and further proteins in DDR with poly(ADP-ribose), ultimately promoting the repair of damaged DNA. PARP inhibitors are particularly efficient in cancers deficient in the homologous recombination repair pathway, which is most frequently caused by loss-of-function mutation in BRCA1 or BRCA2. There are now four FDA-approved PARP inhibitors, and several others are being tested in clinical trials (Lord and Ashworth, 2017Lord C.J. Ashworth A. PARP inhibitors: synthetic lethality in the clinic.Science. 2017; 355: 1152-1158Crossref PubMed Scopus (1325) Google Scholar). A fast-moving set of potentially attractive therapeutic targets are the DNA damage checkpoint kinases, in particular ATR, CHK1, and WEE1. In response to DNA damage, cells stop proliferation at cell-cycle checkpoints, providing time for DNA repair. The G1 checkpoint is frequently abolished in cancer cells and imposes a critical dependency on the G2/M checkpoint. Thus, inhibiting the G2/M checkpoint allows mitotic entry regardless of the presence of substantial DNA damage and can lead to cell death through mitotic catastrophe. Besides their function in the G2/M checkpoint, ATR, CHK1, and WEE1 are vital for DNA replication, in part by suppressing the cell cycle driving CDK activity during S phase, thereby limiting replication stress. While several checkpoint inhibitors are being evaluated in clinical trials, their considerable cytotoxicity can be a clinical hurdle (Dobbelstein and Sørensen, 2015Dobbelstein M. Sørensen C.S. Exploiting replicative stress to treat cancer.Nat. Rev. Drug Discov. 2015; 14: 405-423Crossref PubMed Scopus (191) Google Scholar). In this issue of Cancer Cell, Fang and colleagues suggest that sequential administration of PARPi followed by checkpoint inhibitors can efficiently eliminate tumor cells while ameliorating the cytotoxicity seen with concurrent combined therapy administration (Figure 1) (Fang et al., 2019Fang Y. McGrail D.J. Sun C. Labrie M. Chen X. Zhang D. Ju Z. Vellano C.P. Lu Y. Li Y. et al.Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy.Cancer Cell. 2019; 35 (this issue): 851-867Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). In agreement with previous reports, the authors observed that combination therapy with PARP and WEE1 inhibitors is synergistic in inhibiting tumor cells growth both in vitro and in vivo (Haynes et al., 2018Haynes B. Murai J. Lee J.M. Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition.Cancer Treat. Rev. 2018; 71: 1-7Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, Lallo et al., 2018Lallo A. Frese K.K. Morrow C.J. Sloane R. Gulati S. Schenk M.W. Trapani F. Simms N. Galvin M. Brown S. et al.The combination of the PARP inhibitor olaparib and the WEE1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer.Clin. Cancer Res. 2018; 24: 5153-5164Crossref PubMed Scopus (93) Google Scholar, Lin et al., 2018Lin X. Chen D. Zhang C. Zhang X. Li Z. Dong B. Gao J. Shen L. Augmented antitumor activity by olaparib plus AZD1775 in gastric cancer through disrupting DNA damage repair pathways and DNA damage checkpoint.J. Exp. Clin. Cancer Res. 2018; 37: 129Crossref PubMed Scopus (33) Google Scholar, Meng et al., 2018Meng X. Bi J. Li Y. Yang S. Zhang Y. Li M. Liu H. Li Y. Mcdonald M.E. Thiel K.W. et al.AZD1775 increases sensitivity to olaparib and gemcitabine in cancer cells with p53 mutations.Cancers (Basel). 2018; 10: E149Crossref PubMed Scopus (37) Google Scholar). They use a high-throughput analysis of protein expression and post-translation modification upon treatment with PARPi or WEE1 inhibitors (WEE1i), alone or in combination. In a panel of ten cell lines, including breast, ovarian, and endometrial cancer, they observed a signaling signature corresponding to activation of DDR and G2/M arrest. Consistently, in cell-based assays, treatment with PARPi resulted in increased replication stress, accumulation of DNA damage, and G2/M arrest, which was overridden by combining the PARPi with WEE1i. The majority of cells that entered mitosis upon the combined treatment were γH2AX and cleaved caspase-3 positive. This suggests that the ultimate effect of the combined treatment is checkpoint override followed by lethal mitotic catastrophe. In vivo, in ovarian cancer model OVCAR8, the concurrent therapy with PARPi and WEE1i efficiently inhibited tumor growth, as opposed to only modest effects with PARPi or WEE1i alone. Nonetheless, the combined therapy also exhibited high toxicity to hosts requiring therapy cessation. Notably, the signaling signature triggered by both PARPi and WEE1i alone was maintained for a prolonged time after their removal. Based on this, the authors hypothesized that sequential therapy may retain efficacy while being less toxic than concurrent therapy. The sequential administration of PARPi followed by WEE1i to cancer cells in vitro indeed induced the DNA damage and subsequent mitotic catastrophe to an extent similar to that of concurrent therapy. Importantly, in contrast to concurrent therapy, the sequential therapy induced only modest levels of DNA damage in untransformed MCF-10A cell line and human bone marrow-derived mesenchymal stem cells. The in vitro findings were recapitulated in ovarian cancer models OVCAR8 and PDX in vivo. In these systems, the sequential therapy with PARPi and WEE1i led to inhibition of tumor growth without detectable toxicity, as indicated by weight loss. Interestingly, cells derived from OVCAR8 tumors treated with sequential therapy remained sensitive to PARPi and WEE1i. This indicates that sequential therapy might limit the development of drug resistance, which represents a challenge in treatment regimes with PARP inhibitors alone. What is the underlying mechanism differentiating the output of concurrent versus sequential therapy? The authors hypothesize that reduced toxicity of sequential therapy may be linked to reduced replication stress compared to concurrent therapy. They suggest that in the case of sequential therapy, cells need to be sensitized to efficient treatment with high levels of endogenous replication stress—which is a common hallmark of most cancers (Macheret and Halazonetis, 2015Macheret M. Halazonetis T.D. DNA replication stress as a hallmark of cancer.Annu. Rev. Pathol. 2015; 10: 425-448Crossref PubMed Scopus (438) Google Scholar). In contrast, non-transformed cells exhibit low levels of RS and thus are protected from the cytotoxic effects of the treatment (Figure 1). To support this notion, the authors could show that non-transformed cells become sensitized to sequential therapy if their level of replication stress is artificially enhanced. The new discoveries by Fang et al., 2019Fang Y. McGrail D.J. Sun C. Labrie M. Chen X. Zhang D. Ju Z. Vellano C.P. Lu Y. Li Y. et al.Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy.Cancer Cell. 2019; 35 (this issue): 851-867Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar should greatly stimulate research to exploit sequential approaches. In this regard, further mechanistic studies are warranted to elucidate why sequential therapy with two RS-inducing inhibitors is particularly beneficial. Could it be because both PARP and WEE1 inhibitions increase RS through parallel pathways, allowing stress levels to reach catastrophic levels? The efficacy and favorable toxicity profiles provided by sequential therapy with PARPi and WEE1i imply clinical utility. Now, it will be very important to identify the patients who will obtain the greatest benefit from this new approach. Remarkably, in contrast to therapy with PARPi alone, synergistic activity of PARPi and WEE1i seems to be independent of the status of HR (Fang et al., 2019Fang Y. McGrail D.J. Sun C. Labrie M. Chen X. Zhang D. Ju Z. Vellano C.P. Lu Y. Li Y. et al.Sequential therapy with PARP and WEE1 inhibitors minimizes toxicity while maintaining efficacy.Cancer Cell. 2019; 35 (this issue): 851-867Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). It is thus uncertain whether patients who are already considered for treatment with PARPi should be selected for early clinical trials, just as the impact of germline mutations of BRCA genes is unknown. On the other hand, the cancer types with high levels of endogenous replication stress might represent particularly suitable targets for sequential therapy with PARPi and checkpoint inhibitors. To this end, reliable biomarkers of replication stress will be of importance. Potential candidates can be genetic, based on frequent ovarian cancer genetic changes in oncogenes driving RS such as CCNE1 (Cyclin E) (Wang et al., 2017Wang Y.K. Bashashati A. Anglesio M.S. Cochrane D.R. Grewal D.S. Ha G. McPherson A. Horlings H.M. Senz J. Prentice L.M. et al.Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes.Nat. Genet. 2017; 49: 856-865Crossref PubMed Scopus (155) Google Scholar). Alternatively, new potential biomarker developments could be histone H2AX phosphorylated at Ser139 and CHK1 phosphorylated at Ser345 that are positive in cells under replication stress and can be determined by immunohistochemistry of tumor biopsy specimens. To encourage this notion, the incidence of such markers correlated well with the response to checkpoint inhibitors in c-Myc-driven large B cell lymphoma (Derenzini et al., 2015Derenzini E. Agostinelli C. Imbrogno E. Iacobucci I. Casadei B. Brighenti E. Righi S. Fuligni F. Ghelli Luserna Di Rorà A. Ferrari A. et al.Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma.Oncotarget. 2015; 6: 6553-6569Crossref PubMed Scopus (45) Google Scholar). Our limited understanding of the interplay between PARPi and WEE1i and the risk of potential adverse effects from a fallacious schedule imply that clinical development will have challenges. Despite the above caveats, clinical development of PARPi and WEE1i is highly warranted regardless of the difficulties. B.E. received research funding from NanoString Technologies, Roche, and Novartis and support for travel and accommodations from Roche and MSD. Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining EfficacyFang et al.Cancer CellJune 10, 2019In BriefFang et al. show that sequential inhibition of PARP (PARPi) and WEE1 or ATR has antitumor efficacy similar to concurrent treatment but reduced toxicity due to the persistence of DNA damage on removal of PARPi and differences in basal replication stress between tumor and normal cells, respectively. Full-Text PDF Open Archive