Reference Detail

Ref Type

Journal Article

PMID

(37469254)

Authors

Jiang W, Ouyang X, Li C, Long Y, Chen W, Ji Z, Shen X, Xiang L, Yang H

Title

Targeting PI3Kα increases the efficacy of anti-PD-1 antibody in cervical cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Immunology			2023 Jul 19		Immunology

URL

Abstract Text

Targeting programmed death 1(PD-1) has been approved for relapsed cervical cancer with unsatisfactory clinical efficacy. This study aims to analyse the impact of PI3K pathway activation on tumour immune microenvironment and evaluates the immune sensitization effect by PI3K inhibition in cervical cancer. The effect of PIK3CA mutation on PD-L1 expression and CD8+ T cells differentiation was determined in cervical cancer tissues. Luciferase and ChIP-qPCR/PCR assays were used to determine the transcriptional regulation of PD-L1 by PIK3CA-E545K. The effects of PI3K inhibitor treatment on immune environment in vitro and in vivo were evaluated by RNA sequencing (RNA-seq) and flow cytometry. The efficacy of PI3K inhibitor and anti-PD-1 therapy was assessed in cell-derived xenografts (CDX) and patients-derived xenografts (PDX). PD-L1 overexpression is more frequently observed in elder women with squamous cervical carcinoma. It predicts longer progress-free survival and overall survival. PIK3CA mutation results in increased mRNA and protein levels of PD-L1, the repression of CD8+ T cell differentiation in cervical cancer. Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA-E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer. Specifically, this mutation promotes the expression of PD-L1 by upregulating the transcription factor IRF1. PI3Kα-specific inhibitor markedly activates immune microenvironment by regulating the PD-1/L1-related pathways and promoting CD8+ T cell differentiation and proliferation in Caski-CDXs with PIK3CA-E545K mutation. PI3Kα inhibitor significantly enhances the anti-tumour efficacy of PD-1 blockade in CDXs and PDXs. PIK3CA mutations may predict the response of cervical cancer to PD-1 blockade. The efficacy of PI3Kα inhibitors combined with PD-1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA E545K	cervical cancer	sensitive	Alpelisib + Toripalimab-tpzi	Preclinical - Pdx	Actionable	In a preclinical study, the combination of Piqray (alpelisib) and Loqtorz (toripalimab-tpzi) inhibited proliferation in cell line xenograft models of cervical cancer harboring PIK3CA E545K and in a patient-derived xenograft (PDX) model (PMID: 37469254).	37469254
PIK3CA E545K	cervical cancer	predicted - sensitive	Pembrolizumab	Case Reports/Case Series	Actionable	In a clinical case study, Keytruda (pembrolizumab) treatment resulted in complete remission in a patient with metastatic cervical cancer harboring PIK3CA E545K and moderate tumor mutational burden (TMB) (9.2 mut/Mb) (PMID: 37469254).	37469254
PIK3CA E545K	cervical cancer	predicted - sensitive	Alpelisib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Piqray (alpelisib) increased apoptosis and decreased colony formation in a cervical cancer cell line harboring PIK3CA E545K in culture and decreased tumor cell proliferation and increased CD8-positive T-cell differentiation and proliferation in a cell line xenograft model (PMID: 37469254).	37469254