A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy

Wojtaszek, Jessica L.; Chatterjee, Nimrat; Najeeb, Javaria; Ramos, Azucena; Lee, Minhee; Bian, Ke; Xue, Jenny Y.; Fenton, B.A.; Park, Hyeri; Li, Deyu; Hemann, Michael T.; Hong, Jiyong; Walker, Graham C.; Zhou, Pei

doi:10.1016/j.cell.2019.05.028

Cited by 148 publications

(141 citation statements)

References 38 publications

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“…A potential approach, suggested by experiments in laboratory settings, has been to disrupt pol ζ function to enhance chemotherapeutic effectiveness [33][34][35]. For example, an inhibitor that impairs the interaction of pol ζ with the master regulator REV1 has been developed that sensitizes cancer cells and xenograft tumors to cisplatin treatment [36]. Our work suggests that such inhibitors might also induce an interferon response.…”

Section: An Innate Immune Response Cause By Loss Of Pol ζ Functionmentioning

confidence: 88%

Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

Martin

Tomida

Wood

2020

Preprint

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DNA polymerase pol ζ is regarded as a specialized DNA polymerase for bypass of DNA lesions. In mammalian cells, pol ζ also contributes to genomic stability during normal DNA replication. Disruption of Rev3l (the catalytic subunit of pol ζ) is toxic to cells and mice, with increased constitutive chromosome damage, including micronuclei. As the cellular manifestations of this genomic stress have remained unexplored, we measured genome-wide transcriptional changes by RNA-seq in pol ζ-defective cells. Expression of 1117 transcripts was altered by 4-fold or more in Rev3l knockout mouse embryonic fibroblasts (MEFs), with a pattern showing an induction of an innate immune response.We validated the increased expression of known interferon-stimulated genes (ISG) at the mRNA and protein levels. We found that the cGAS-STING axis, which senses cytosolic DNA, drives ISG expression in Rev3l knockout MEFs. These results reveal a new genome protective function of pol ζ and indicate that inhibition of pol ζ may be therapeutically useful by simultaneously increasing sensitivity to genotoxins and inducing a cytotoxic innate immune response.

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Section: An Innate Immune Response Cause By Loss Of Pol ζ Functionmentioning

confidence: 88%

Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

Martin

Tomida

Wood

2020

Preprint

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“…Though this damage tolerance pathway benefits the cell by relieving stalled replication, unregulated TLS activity can detrimentally contribute to mutagenesis and resistance to DNAdamaging cancer therapies. Recent advances have addressed these drawbacks through identification of small molecule inhibitors which target Pol-Pol interactions and/or disrupt mutagenic TLS activity, supplementing the effectiveness of current chemotherapeutic drugs (62)(63)(64)(65)(66)(67)(68). These studies provide a promising new approach for mitigating the role of TLS in chemoresistance and provide an exciting incentive for furthering our understanding of the kinetic and structural foundations of TLS.…”

Section: Discussionmentioning

confidence: 99%

A hand-off of DNA between archaeal polymerases allows high-fidelity replication to resume at a discrete intermediate three bases past 8-oxoguanine

Cranford

Kaszubowski

Trakselis

2020

Preprint

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During DNA replication, the presence of 8-oxoguanine (8-oxoG) lesions in the template strand cause the high-fidelity (HiFi) DNA polymerase (Pol) to stall. An early response to 8-oxoG lesions involves 'on-the-fly' translesion synthesis (TLS), in which a specialized TLS Pol is recruited and replaces the stalled HiFi Pol for bypass of the lesion. The length of TLS must be long enough for effective bypass, but it must also be regulated to minimize replication errors by the TLS Pol. The exact position where the TLS Pol ends and the HiFi Pol resumes (i.e. the length of the TLS patch) has not been described. We use steady-state and presteady-state kinetic assays to characterize lesion bypass intermediates formed by different archaeal polymerase holoenzyme complexes that include PCNA123 and RFC. After bypass of 8-oxoG by TLS PolY, products accumulate at the template position three base pairs beyond the lesion. PolY is catalytically poor for subsequent extension from this +3 position beyond 8-oxoG, but this inefficiency is overcome by rapid extension of HiFi PolB1. The reciprocation of Pol activities at this intermediate indicates a defined position where TLS Pol extension is limited and where the DNA substrate is handed back to the HiFi Pol after bypass of 8-oxoG.

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“…By targeting the genetic differences of cancer cells, several molecule-targeting drugs, such as Afatinib and Gefitinib, had been approved by U.S. FDA and shown their promising therapeutic activity against various cancers (Cataldo et al, 2011;Hirsch and Bunn, 2012). However, the therapeutic strategies of "one drug-hits-one target-treats-one disease" still face significant challenges as the drug resistance (To et al, 2019;Wojtaszek et al, 2019). Recent studies suggested that targeting the multiple targets might be a practicable approach to ameliorate the therapeutic activity and selectivity, meanwhile preventing the drug resistance (To et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers

Chen

Bao²,

Weng

et al. 2020

Front. Pharmacol.

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In the past decades, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) had been proved as an effective treatment strategy for the patients with EGFRmutated non-small-cell lung cancer (NSCLC). However, the tolerance for the EGFR-TKI always occurred after continuous administration for a period of time and limiting the application of these drugs. Activation of FGFR1 signaling pathway was one of the important escape mechanisms for EGFR-TKI resistant in NSCLC. Here, a novel dual inhibitor of EGFR L858R/T790M and FGFR1, compound15c, was found and can efficiently overcame the EGFR-TKI resistance via its simultaneous inhibition of their kinase activities. Comparison with EGFR L858R/T790M and FGFR1 inhibitor treatment alone or combined revealed that the inhibition of EGFR L858R/T790M and FGFR1 activity by 15c was responsible for surmounting the intrinsic EGFR-TKI resistance in EGFR L858R/T790M-mutated H1975 cells and the acquired resistance in Afatinib-tolerant PC9 cells (AFA-PC9). Flow Cytometry and Caspase3 activity analysis assay showed that 15c induced significant the early apoptosis of H1975 cells. Xenograft tumor formation in BALB/c mice induced by a H1975 cells was suppressed by 15c treatment, with no changes in animal body weight. Generally, 15c may act as a new-generation EGFR-TKI for the therapy of NSCLC patients suffering a resistance to current TKI.

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A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy

Cited by 148 publications

References 38 publications

Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

Deficiency in Translesion DNA Polymerase ζ Induces an Innate Immune Response

A hand-off of DNA between archaeal polymerases allows high-fidelity replication to resume at a discrete intermediate three bases past 8-oxoguanine

Compound 15c, a Novel Dual Inhibitor of EGFRL858R/T790M and FGFR1, Efficiently Overcomes Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Resistance of Non-Small-Cell Lung Cancers

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