Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response

Willis, Sophie E.; Winkler, C; Roudier, Martine P.; Baird, Tarrion; Marco-Casanova, Paola; Jones, Emma V.; Rowe, Philip; Rodriguez‐Canales, Jaime; Angell, Helen K.; Ng, Felicia S.L.; Waring, Paul; Hodgson, Darren; Ledermann, Jonathan A.; Weberpals, Johanne I.; Dean, Emma; Barrett, J. Carl; Pierce, Andrew J.; Leo, Elisabetta; Jones, Gemma N.

doi:10.1038/s41416-021-01560-1

Cited by 26 publications

(19 citation statements)

References 42 publications

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“…This data suggests that there can be additional dependencies for synergism, which is likely related to each cell line’s repertoire of mutational signatures. As supported by our perturbation screen and previous studies, decreased SLFN11 expression is responsible for drug resistance to DNA-damaging agents (33). Based on the publicly available data set (merav.wi.mit.edu/) (34), SLFN11 expression is significantly lower in SNU16 cells compared to SNU5 cells, which may be the cause of the breached correlation between ABCG2 expression and synergism (Figure S7F).…”

Section: Discussionsupporting

confidence: 83%

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy

Leylek,

Honeywell,

Lee

et al. 2023

Preprint

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The rational combination of anticancer agents is critical to improving patient outcomes in cancer. Nonetheless, most combination regimens in the clinic result from empirical methodologies disregarding insight into the mechanism of action and missing the opportunity to improve therapy outcomes incrementally. Deciphering the genetic dependencies and vulnerabilities responsible for synergistic interactions is crucial for rationally developing effective anticancer drug combinations. Hence, we screened pairwise pharmacological interactions between molecular-targeted agents and conventional chemotherapeutics and examined the genome-scale genetic dependencies in gastric adenocarcinoma cell models. Since this type of cancer is mainly chemoresistant and incurable, clinical situations demand effective combination strategies. Our pairwise combination screen revealed SN38/erlotinib as the drug pair with the most robust synergism. Genome-wide CRISPR screening and a shRNA-based signature assay indicated that the genetic dependency/vulnerability signature of SN38/erlotinib was not divergent from that of SN38 alone. Additional investigation revealed that the enhanced cell death with improved death kinetics caused by the SN38/erlotinib combination is surprisingly due to erlotinib’s off-target effect that inhibits ABCG2, not its on-target effect on EGFR. These findings demonstrate the importance of assessing off-target effects in addition to the perceived on-target effects of a drug. Our results confirm that a genetic dependency signature different from the single-drug application may not be necessary for the synergistic interaction of molecular-targeted agents with conventional chemotherapeutics in gastric adenocarcinoma. The findings also demonstrated the efficacy of functional genomics approaches in unveiling biologically validated mechanisms of pharmacological interactions.SignificanceFunctional genomics approaches efficiently demonstrated that a divergence in genetic dependency/vulnerability signature is not essential for the synergistic interaction of molecular-targeted agents and conventional chemotherapeutic combinations in gastric adenocarcinoma.

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Section: Discussionsupporting

confidence: 83%

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy

Leylek,

Honeywell,

Lee

et al. 2023

Preprint

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“…While the mechanisms of SLFN11‐mediated cell killing are not fully understood, the importance of SLFN11 in drug sensitivity is validated in various settings 47 , 48 , 49 , 50 (see recent reviews 38 , 51 ). Patient data are also accumulating with a broad type of cancers including breast cancer, 50 , 52 ovarian cancer, 53 gastric cancer, 54 bladder cancer, 55 small cell lung cancer, 56 esophageal cancer, 57 and prostate cancer. 58 Notably, most of these data have been obtained without considering the presence or absence of BRCA or HR deficiency.…”

Section: Slfn11 Is a Common Sensitizer To Platinum Derivat...mentioning

confidence: 99%

“…Recently, the group of AstraZeneca examined the effect of SLFN11 on olaparib sensitivity. 56 They first showed that patients with high‐SLFN11 tumors had significantly longer overall survival when treated with first‐line platinum and etoposide in small cell lung cancer. Although the role of SLFN11 was uncertain in their cohort of high‐grade serous ovarian cancers treated with paclitaxel‐platinum, they found that high levels of SLFN11 were associated with improved clinical outcomes with olaparib treatment.…”

Section: Does Slfn11 Need Brca ...mentioning

confidence: 99%

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Reconsidering the mechanisms of action of PARP inhibitors based on clinical outcomes

Onji

Murai

2022

Cancer Science

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PARP inhibitors (PARPis) were initially developed as DNA repair inhibitors that inhibit the catalytic activity of PARP1 and PARP2 and are expected to induce synthetic lethality in BRCA ‐ or homologous recombination (HR)‐deficient tumors. However, the clinical indications for PARPis are not necessarily limited to BRCA mutations or HR deficiency; BRCA wild‐type and HR‐proficient cancers can also derive some benefit from PARPis. These facts are interpretable by an additional primary antitumor mechanism of PARPis named PARP trapping, resulting from the stabilization of PARP‐DNA complexes. Favorable response to platinum derivatives (cisplatin and carboplatin) in preceding treatment is used as a clinical biomarker for some PARPis, implying that sensitivity factors for platinum derivatives and PARPis are mainly common. Such common sensitivity factors include not only HR defects (HRD) but also additional factors. One of them is Schlafen 11 ( SLFN11 ), a putative DNA/RNA helicase, that sensitizes cancer cells to a broad type of DNA‐damaging agents, including platinum and topoisomerase inhibitors. Mechanistically, SLFN11 induces a lethal replication block in response to replication stress (ie, DNA damage). As SLFN11 acts upon replication stress, trapping PARPis can activate SLFN11. Preclinical models show the importance of SLFN11 in PARPi sensitivity. However, the relevance of SLFN11 in PARPi response is less evident in clinical data compared with the significance of SLFN11 for platinum sensitivity. In this review, we consider the reasons for variable indications of PARPis resulting from clinical outcomes and review the mechanisms of action for PARPis as anticancer agents.

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“…The ongoing model is that SLFN11 is recruited to replication forks under replication stress where the replicative helicases and polymerases are uncoupled, which causes the formation of extended RPA-coated ssDNA that recruits SLFN11 to irreversibly arrests replication. SLFN11 also confers hypersensitivity to PARPis in pre-clinical models [9,29,30], and a recent clinical study analyzing the effects of SLFN11 on olaparib sensitivity in patients with ovarian cancer showed that high SLFN11 expression is associated with improved clinical outcome [31]. Notably, subgroup analyses revealed that only patients with both BRCA mutations and high SLFN11 expression bene ted signi cantly from olaparib treatment.…”

Section: Introductionmentioning

confidence: 99%

Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks

Murai,

Onji,

Tate

et al. 2024

Preprint

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The preferential response to PARP inhibitor (PARPi) olaparib in BRCA-deficient and Schlafen 11 (SLFN11)-expressing ovarian cancers has been documented, yet the underlying molecular mechanisms remain unclear. As the accumulation of single-strand DNA (ssDNA) gaps behind replication forks is key for the lethality induced by PARPis, we investigated the combined effects of SLFN11 expression and BRCA deficiency on PARPis sensitivity and ssDNA gap formation in human cancer cells. PARPis increased chromatin-bound RPA2 and ssDNA gaps in SLFN11-expressing cells and even more in cells with BRCA1 or BRCA2 deficiency. SLFN11 was co-localized with chromatin-bound RPA2 under PARPis treatment, with enhanced recruitment in BRCA2-deficient cells. Notably, the chromatin-bound SLFN11 under PARPis did not block replication, contrary to its function under replication stress. SLFN11 recruitment was attenuated by the MRE11 inhibitor, mirin. Hence, under PARPis treatment, MRE11 expression and BRCA deficiency lead to ssDNA gaps behind replication forks, where SLFN11 binds and increases their formation. Ovarian cancer patients who super-responded (progression-free survival > 2 years) to olaparib maintenance therapy had a significantly higher SLFN11-positivity than short-responders (< 6 months). Our findings provide a mechanistic understanding of the favorable responses to PARPis in SLFN11-expressing and BRCA-deficient tumors and highlight the clinical implications of SLFN11.

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Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response

Cited by 26 publications

References 42 publications

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy

Reconsidering the mechanisms of action of PARP inhibitors based on clinical outcomes

Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks

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