Novel therapeutic combinations with PARP inhibitors for small cell lung cancer: A bench-to-bedside review

Xiong, Jiaqi; Barayan, Ranya; Louie, Alexander V.; Lok, Benjamin H.

doi:10.1016/j.semcancer.2022.07.008

Cited by 11 publications

(3 citation statements)

References 180 publications

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“…This study validated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors at the cellular level. PARP1 inhibitors for cancer therapy have experienced rapid growth, and many of them are being evaluated in clinical trials for the treatment of solid tumours, including (non) small-cell lung cancer, prostate cancer, and gastric cancer 30 , 31 . However, the narrow applicability of PARP1 inhibitors and acquired resistance limit their further application in cancer.…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells

Chen,

Ren,

Zhang

et al. 2024

Journal of Enzyme Inhibition and Medicinal Chemistry

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Specifically inducing the degradation of acidic nucleoplasmic DNA-binding protein 1 (And1) is a promising antitumor strategy. Our previous study identified Bazedoxifene (BZA) and CH3 as specific And1 degraders and validated their activity in reversing radiotherapy resistance in vitro and in vivo . However, unelucidated structure-activity relationships and moderate activity have limited their application. In this study, 27 novel CH3 derivatives were designed and synthesised based on the cavity topology of the WD40 domain of And1. Among them, A15 with a “V” conformation significantly induced And1 degradation in NSCLC cells. In addition, this study demonstrated a potential synthetic lethal effect of And1 degraders and PARP1 inhibitors. 1 µM of Olaparib in combination with 5 µM of A15 significantly inhibited the proliferation of A549 and H460 cells. Overall, these compounds are valuable tools for elucidating And1 biology, and their special spatial conformation make them promising candidates for future optimisation studies.

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Section: Discussionmentioning

confidence: 99%

Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells

Chen,

Ren,

Zhang

et al. 2024

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Lung cancer is one of the most common malignant tumors, with increasing incidence and mortality rates year by year, posing a significant threat to human health and life safety. , Early symptoms of lung cancer are often inconspicuous, and most patients are diagnosed at an advanced stage, where chemotherapy becomes their primary treatment option. , The first-line chemotherapy drugs mainly include cytotoxic drugs and targeted drugs . Cytotoxic drugs inhibit tumor growth by directly killing tumor cells or blocking the synthesis of nucleic acids, proteins, etc.…”

Section: Introductionmentioning

confidence: 99%

Study on the Mechanism of Yadanzi Oil in Treating Lung Cancer Based on Network Pharmacology and Molecular Docking Technology

Liu,

Shen,

et al. 2024

ACS Omega

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Brucea javanica oil emulsion (BJOE) is a compound Chinese medicine used for treating various cancers, such as lung cancer. However, the exact mechanism of its antilung cancer active ingredient remains unclear. This study aims to explore and validate the effective active ingredients and mechanism of action of BJOE in the treatment of lung cancer through network pharmacology, molecular docking technology, and cell experiments. The results showed that there were 13 active ingredients, 136 target genes, and 42 disease target-coexpressed genes in BJOE. The molecular docking results indicated that the main active components of the oil emulsion, YD1 (β-sitosterol), YD2 (luteolin), and YD3 (bruceitol), could stably bind to TP53 and MAPK1. Furthermore, the commercially available β-sitosterol luteolin was used as a representative compound to conduct cell experiments to verify its anticancer activity and mechanism. It was found that luteolin can inhibit the proliferation better than β-sitosterol and the activity of lung cancer cells by regulating the expression of related proteins through the P53/MAPK1 signaling pathway. This study combines network pharmacology prediction with experiments to demonstrate the "multicomponent, multitarget, multipathway" approach of B. javanica oil emulsion in treating lung cancer.

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“…Approximately 15% of newly diagnosed lung cancer cases are small cell lung cancer (SCLC) patients. And it is characterized by its aggressive nature, early metastasis, and generally unfavorable prognosis ( 1 , 2 ). Unlike non-small cell lung cancer (NSCLC), development in the therapy strategy of SCLC has been relatively slower.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study

Xie,

Xu,

Cai

et al. 2024

Transl Lung Cancer Res

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Background The prognosis of small cell lung cancer (SCLC) patients is poor, and the standard first-line treatment for limited-stage small cell lung cancer (LS-SCLC) is still chemotherapy and thoracic radiotherapy. The primary objectives of our study were to confirm the superior efficacy of first-line immune checkpoint inhibitors (ICIs) plus etoposide and platinum (EP) for LS-SCLC and find crucial biomarkers. Methods We analyzed LS-SCLC patients from three medical centers, employing propensity score matching for group comparability. Survival outcomes were estimated by Kaplan-Meier and Cox regression analyses. Additionally, we conducted univariate and multivariate analyses to investigate potential predictive factors. Results Among 150 patients in our study, we successfully matched 41 pairs. The median overall survival (OS) was 29.5 months in the EP + ICIs group and 20.0 months in the EP group {hazard ratio (HR) =0.64 [95% confidence interval (CI): 0.41–1.02], P=0.059}. The median progression-free survival (PFS) was significantly extended in the EP + ICIs group (14.6 months), compared to the EP group (8.6 months) [HR =0.42 (95% CI: 0.28–0.63), P<0.001]. After matching, patients receiving chemo-immunotherapy had a median OS of 36.1 months, significantly surpassing those receiving chemotherapy alone (19.0 months) [HR =0.51 (95% CI: 0.28–0.93), P=0.02]. And the patients in the EP + ICIs group also had longer PFS after matching [HR =0.42 (95% CI: 0.25–0.71), P=0.001]. No significant difference in the objective response rate (ORR) and treatment-related adverse events (trAEs) between the two groups was found (ORR: EP: 81.0%, EP + ICIs: 90.0%, P=0.14; trAEs: EP: grade 1–2, 49.3%; grade 3–4, 42.5%; EP + ICIs: grade 1–2, 40.0%; grade 3–4, 49.1%, P=0.62). The multivariate analysis presented that the history of immunotherapy [EP + PD-1 inhibitors: HR =0.33 (95% CI: 0.17–0.62), P=0.001; EP + PD-L1 inhibitors: HR =0.18 (95% CI: 0.06–0.60), P=0.005] and baseline lung immune prognostic index (LIPI) [intermediate: HR =2.22 (95% CI: 1.20–4.13), P=0.01; poor: HR =2.03 (95% CI: 0.71–5.77), P=0.18] were independent prognostic factors for PFS among all LS-SCLC cases. However, no independent prognostic factor was identified for OS. Conclusions Our real-world data showed promising clinical efficacy and tolerable safety of first-line programmed cell death protein 1 (PD-1) inhibitors or programmed cell death ligand 1 (PD-L1) inhibitors in cases with LS-SCLC. Additionally, LIPI may serve as a valuable prognostic factor.

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Novel therapeutic combinations with PARP inhibitors for small cell lung cancer: A bench-to-bedside review

Cited by 11 publications

References 180 publications

Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells

Design, synthesis, and evaluation of novel stilbene derivatives that degrade acidic nucleoplasmic DNA-binding protein 1 (And1) and synergize with PARP1 inhibitor in NSCLC cells

Study on the Mechanism of Yadanzi Oil in Treating Lung Cancer Based on Network Pharmacology and Molecular Docking Technology

Efficacy and safety of first-line PD-L1/PD-1 inhibitors in limited-stage small cell lung cancer: a multicenter propensity score matched retrospective study

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