Predictive value of ZFHX4 mutation for the efficacy of immune checkpoint inhibitors in non-small cell lung cancer and melanoma.

IF 3 3区 医学 Q2 ONCOLOGY Investigational New Drugs Pub Date : 2024-10-05 DOI:10.1007/s10637-024-01477-5
Cong Fu, Haoran Gu, Lin Sun, Zhouyu Wang, Qin Zhang, Ningning Luo, Dongsheng Chen, Tong Zhou
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Abstract

Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.

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ZFHX4突变对免疫检查点抑制剂在非小细胞肺癌和黑色素瘤中疗效的预测价值。
研究表明,锌指同源染色体 4(ZFHX4)可能是影响恶性肿瘤预后的一个因素。然而,人们对ZFHX4突变与免疫检查点抑制剂(ICIs)在非小细胞肺癌(NSCLC)和黑色素瘤中的疗效之间的关系知之甚少。三个公开的ICIs治疗NSCLC队列分为发现队列(75人)和验证队列(62人),用于评估ZFHX4突变与ICIs在NSCLC中疗效的关系。7个经ICIs治疗的黑色素瘤队列(n=418)用于分析ZFHX4突变与黑色素瘤免疫疗法疗效之间的关系。癌症基因组图谱(TCGA)中的NSCLC和皮肤黑色素瘤(SKCM)队列被用来研究其潜在机制。在NSCLC队列中,ZFHX4突变型(ZFHX4-Mut)患者的客观反应率(ORR)(P<0.01)和无进展生存期(PFS)(P<0.05)均优于ZFHX4野生型(ZFHX4-WT)患者。在黑色素瘤队列中,携带ZFHX4-突变型的患者有更高的ORR(P = 0.042)和更长的总生存期(OS)(P = 0.011)。此外,携带ZFHX4-突变基因的非小细胞肺癌和黑色素瘤患者的肿瘤突变负荷(TMB)较高(P = 0.011)。
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来源期刊
CiteScore
7.60
自引率
0.00%
发文量
121
审稿时长
1 months
期刊介绍: The development of new anticancer agents is one of the most rapidly changing aspects of cancer research. Investigational New Drugs provides a forum for the rapid dissemination of information on new anticancer agents. The papers published are of interest to the medical chemist, toxicologist, pharmacist, pharmacologist, biostatistician and clinical oncologist. Investigational New Drugs provides the fastest possible publication of new discoveries and results for the whole community of scientists developing anticancer agents.
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