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SEC61G assists EGFR-amplified glioblastoma to evade immune elimination.

ABSTRACT: Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical regulator facilitating GBM immune evasion and tumor growth. We found that SEC61G is always coamplified with EGFR and is highly expressed in GBM. As an essential subunit of the SEC61 translocon complex, SEC61G promotes translocation of newly translated immune checkpoint ligands (ICLs, including PD-L1, PVR, and PD-L2) into the endoplasmic reticulum and promotes their glycosylation, stabilization, and membrane presentation. Depletion of SEC61G promotes the infiltration and cytolytic activity of CD8⁺ T cells and thus inhibits GBM occurrence. Further, SEC61G inhibition augments the therapeutic efficiency of EGFR tyrosine kinase inhibitors in mice. Our study demonstrates a critical role of SEC61G in GBM immune evasion, which provides a compelling rationale for combination therapy of EGFR-amplified GBMs.

SUBMITTER: Zeng K

PROVIDER: S-EPMC10410745 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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SEC61G assists EGFR-amplified glioblastoma to evade immune elimination.

Zeng Kunlin K Zeng Yu Y Zhan Hongchao H Zhan Ziling Z Wang Li L Xie Yuxin Y Tang Yanqing Y Li Cuiying C Chen Yanwen Y Li Shangbiao S Liu Ming M Chen Xiaoxia X Liang Li L Deng Fan F Song Ye Y Zhou Aidong A

Proceedings of the National Academy of Sciences of the United States of America 20230731 32

Amplification of chromosome 7p11 (7p11) is the most common alteration in primary glioblastoma (GBM), resulting in gains of epidermal growth factor receptor (EGFR) copy number in 50 to 60% of GBM tumors. However, treatment strategies targeting EGFR have thus far failed in clinical trials, and the underlying mechanism remains largely unclear. We here demonstrate that EGFR amplification at the 7p11 locus frequently encompasses its neighboring genes and identifies SEC61G as a critical ...[more]

PMID: 37523556

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Project description:BackgroundThe treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors like erlotinib has not met expectations for glioblastoma therapy, even for EGFR-overexpressing tumors. We determined possible mechanisms of therapy resistance using the unique BS153 glioblastoma cell line, which has retained amplification of the egfr gene and expression of EGFR variant (v)III.MethodsFunctional effects of erlotinib, gefitinib, and cetuximab on BS153 proliferation, migration, and EGFR-dependent signal transduction were systematically compared in vitro. The tumor-initiating capacity of parental and treatment-resistant BS153 was studied in Naval Medical Research Institute/Foxn1(nu) mice. Potential mediators of resistance were knocked down using small interfering (si)RNA.ResultsErlotinib and gefitinib inhibited proliferation and migration of BS153 in a dose-dependent manner, whereas cetuximab had no effect. BS153 developed resistance to erlotinib (BS153(resE)) but not to gefitinib. Resistance was associated with strong upregulation of EGFRvIII and subsequent activation of the phosphatidylinositol-3-OH kinase (PI3K) pathway in BS153(resE) and an increased expression of the regulatory 110-kDa delta subunit of PI3K (p110δ). Knockdown of EGFRvIII in BS153(resE) largely restored sensitivity to erlotinib. Targeting PI3K pharmacologically caused a significant decrease in cell viability, and specifically targeting p110δ by siRNA partially restored erlotinib sensitivity in BS153(resE). In vivo, BS153 formed highly invasive tumors with an unusual growth pattern, displaying numerous satellites distant from the initial injection site. Erlotinib resistance led to delayed onset of tumor growth as well as prolonged overall survival of mice without changing tumor morphology.ConclusionsEGFRvIII can mediate resistance to erlotinib in EGFR-amplified glioblastoma via an increase in PI3Kp110δ. Interfering with PI3Kp110δ can restore sensitivity toward the tyrosine kinase inhibitor.

Project description:Abstract BACKGROUND Depatuxizumab mafodotin (depatux-m, formerly ABT-414), is an antibody-drug conjugate comprised of an EGFR-targeted antibody, a non-cleavable linker maleimidocaproyl, and the microtubule inhibitor monomethylauristatin F. Promising antitumor activity of depatux-m was observed in patients with glioblastoma (GBM) in Phase 12 studies. Dosage of depatux-m is limited by ocular side effects (OSE), such as blurred vision, dry eye, and photophobia from corneal epitheliopathy, which are generally reversible after dose reduction or drug discontinuation. This Phase 3b study evaluates depatux-m-related OSE management strategies used in depatux-m clinical trials. METHODS This open-label study will enroll approximately 90 patients with newly diagnosed, histologically confirmed, grade IV GBM that is epidermal growth factor receptor (EGFR)-amplified. Patients will receive depatux-m during the chemoradiation phase (radiation and temozolomide [TMZ]), and during adjuvant therapy with TMZ. Patients are randomized to one of three prophylactic ocular treatments: standard steroids (SS), SS with vasoconstrictors and cold compress (VC), or enhanced steroids (ES) with VC. Primary objective is to evaluate these prophylactic strategies for their effect on the proportion of patients requiring a change in OSE management due to inadequate control of OSEs, defined as either a 3-line decline in visual acuity from baseline or Grade 3 OSE severity on the Corneal Epithelial Adverse Event (CEAE) activities of daily living-based scale. Inadequate control with initial prophylactic regimen will trigger a switch to the addition of bandage contact lenses (BCL). Secondary objective assesses change in OSE management due to inadequate control of OSEs by BCL, defined as percentage of patients with Grade 3 CEAE that will trigger transition of patient to investigator discretion regimen (depatux-m interruption/dose reduction, VC prophylaxis, or ES prophylaxis). ClinicalTrials.gov: NCT03419403.

Dataset Information

SEC61G assists EGFR-amplified glioblastoma to evade immune elimination.

Publications

SEC61G assists <i>EGFR</i>-amplified glioblastoma to evade immune elimination.

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