m6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer

Abstract

Background Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy—with or without immune checkpoint inhibitors (anti-PDs)—is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood. Methods We systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts—including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients’ responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. Results We observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75–9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. Conclusions Our results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.

Effect of Kaempferol on the Biological Behavior of Human Colon Cancer via Regulating MMP1, MMP2, and MMP9

“…In addition, kaempferol can inhibit the occurrence and development of prostate cancer by inhibiting the expression of Ki67 [ 31 ]. Kaempferol and TGF- β receptor (ALK5) binding inhibits the phosphorylation and translocation of Smad2 and reduces the expression of Smad4, thus inhibiting the proliferation, migration, and invasion of tumor cells [ 32 ]. To date, chemotherapy is still an important treatment for patients with colorectal cancer.…”

Expression patterns of platinum resistance-related genes in lung adenocarcinoma and related clinical value models

“…It is mainly regulated by the m6A methylation regulator ( Chen et al, 2019 ; Liu et al, 2019 ). Previous studies have focused on the relationship between m6A and the occurrence and development of LUAD ( Li et al, 2022 ; Ma et al, 2022 ; Qian et al, 2021 ), or the relationship between the m6A regulatory factor and chemotherapy resistance of small cell lung cancer ( Zhang et al, 2021a ; Zhang et al, 2021b ). Some studies have also found that the m6A regulatory factor is closely related to LUAD resistance to erlotinib ( Li K et al, 2021 ).…”

Systemic Therapy for Small-Cell Lung Cancer: ASCO-Ontario Health (Cancer Care Ontario) Guideline

“…111 In another study that assessed tumors from 231 patients with LS-SCLC who were treated with chemoradiotherapy, CDK4 and GATA6 expression as well as EGFR-activating mutations were prognostic for poorer OS (HR, 2.18; HR, 2.39; HR, 2.26). 160 Additionally, Zhang et al 109 created a prognostic signature based on N 6 -methyladenosine (m 6 A), an epigenetic modification involved in tumorigenesis and immune function. Among 265 patients with LS-SCLC, those with a high m6A score had decreased OS (HR, 5.19; 95% CI, 2.75 to 9.77; P < .001), a finding that was validated in two independent cohorts.…”