KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma

Chen, Nan; Fang, Wenfeng; Zhang, Lin; Peng, Peijian; Wang, Juan; Zhan, Jie; Hong, Shaodong; Huang, Jiaxing; Liu, Lin; Jin, Sheng; Zhou, Ting; Chen, Ying; Zhang, Hongyu; Zhang, Li

doi:10.1007/s00262-017-2005-z

Cited by 220 publications

(190 citation statements)

References 42 publications

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“…Specific siRNA sequences targeting the EGFR gene (si‐EGFR) were synthetized by Beijing Aoke Peak Biotechnology (Beijing, China). Expression vectors and siRNA transfections were carried out as described .…”

Section: Methodsmentioning

confidence: 99%

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Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Guo

Wang

et al. 2019

Cancer Science

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Some driver gene mutations, including epidermal growth factor receptor ( EGFR ), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 ( PD ‐L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD ‐L1 expression regulation in non‐small‐cell lung cancer ( NSCLC ) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD ‐L1 overexpression and phosphorylation of AKT and ERK , especially with increased protein levels of phospho‐IκBα (p‐IκBα) and hypoxia‐inducible factor‐1α (HIF‐1α). Flow cytometry results showed stronger membrane co‐expression of EGFR and PD ‐L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR . Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK / ERK , PI 3K/ AKT , mTOR /S6, IκBα, and HIF ‐1α indicated strong accordance among protein levels of PD ‐L1, p‐IκBα, and HIF ‐1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p‐IκBα, HIF ‐1α, and PD ‐L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p‐IκBα, HIF ‐1α, and PD ‐L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR . Non‐small‐cell lung cancer tissues with either p‐IκBα or HIF ‐1α positive staining were more likely to possess elevated PD ‐L1 expression compared with tissues scored negative for both p‐IκBα and HIF ‐1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF ‐κB and HIF ‐1α in PD ‐L1 expression regulation by EGFR mutants in NSCLC .

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Section: Methodsmentioning

confidence: 99%

“…Specific siRNA sequences targeting the EGFR gene (si-EGFR) 22,23 were synthetized by Beijing Aoke Peak Biotechnology (Beijing, China).…”

Section: Expression Vectors and Sirna Transfectionmentioning

confidence: 99%

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Guo

Wang

et al. 2019

Cancer Science

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“…Emerging evidence suggests that coexistence of driver mutations in NSCLC is frequently associated with higher PD-L1 expression. Previous studies have shown EGFR mutations [14][15][16], ALK rearrangements [27,28], and KRAS mutations [29] were positively correlated with PD-L1 expression. However, the regulatory mechanism in wild-type EGFR tumors is still unknown.…”

Section: Discussionmentioning

confidence: 89%

“…Thus, in our study, we selected A549 and H460 cell lines, which are both wild‐type for EGFR but have different levels of PD‐L1 expression. To explore the potential regulatory mechanisms of higher PD‐L1 levels in H460 cells, we examined the downstream signaling pathways, as previously reported ; the results showed PD‐L1 upregulation was associated with the activation of STAT3, AKT, and ERK. By inhibiting p‐STAT3, p‐AKT, and p‐ERK, PD‐L1 was significantly decreased.…”

Section: Discussionmentioning

confidence: 99%

E3 ubiquitin ligases Cbl‐b and c‐Cbl downregulate PD‐L1 in EGFR wild‐type non‐small cell lung cancer

Wang

Che

et al. 2018

FEBS Letters

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Anti-PD-1/PD-L1 therapies have demonstrated prominent clinical effects in the treatment of non-small cell lung cancer (NSCLC). However, limited understanding of the regulatory mechanisms of PD-L1 has become one of the biggest challenges for further improving efficacy. In this study, we observed that in wild-type EFGR cell lines A549 and H460, the ubiquitin ligases Cbl-b and c-Cbl inhibit PD-L1 by inactivating STAT, AKT, and ERK signaling. MiR-181a and miR-940 were screened and validated to target Cbl-b and c-Cbl, respectively. Furthermore, in NSCLC tissues, the expression of Cbl-b/c-Cbl is negatively correlated with PD-L1 expression. Taken together, these findings indicated a new regulatory mechanism for PD-L1 in wild-type EGFR NSCLC cell lines by Cbl-b and c-Cbl.

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“…Efficacy analyses could be performed in patients with pancreatic or colorectal cancers, because RAS mutations are more frequent in those types of cancers. Furthermore, in lung adenocarcinoma, it has been demonstrated that KRAS mutation induces the expression of programmed death ligand 1 (PD-L1) [23, 24]. Accordingly, combination therapy of Salirasib with an anti-PD-1 agent may enhance the anti-cancer efficacy.…”

Section: Discussionmentioning

confidence: 99%

An early clinical trial of Salirasib, an oral RAS inhibitor, in Japanese patients with relapsed/refractory solid tumors

Furuse

Kurata

Okano

et al. 2018

Cancer Chemother Pharmacol

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PurposePatients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy.MethodsSalirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen.ResultsA total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1–13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79–373).ConclusionSalirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation.Clinical trial registrationJAPIC Clinical Trials Information; JapicCTI-121751.Electronic supplementary materialThe online version of this article (10.1007/s00280-018-3618-4) contains supplementary material, which is available to authorized users.

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KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma

Cited by 220 publications

References 42 publications

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

Hypoxia‐inducible factor‐1α and nuclear factor‐κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non‐small‐cell lung cancer cells

E3 ubiquitin ligases Cbl‐b and c‐Cbl downregulate PD‐L1 in EGFR wild‐type non‐small cell lung cancer

An early clinical trial of Salirasib, an oral RAS inhibitor, in Japanese patients with relapsed/refractory solid tumors

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