Integrin-Src-YAP1 signaling mediates the melanoma acquired resistance to MAPK and PI3K/mTOR dual targeted therapy

Yu, Chunhua; Zhang, Min; Song, Jing; Zheng, Xiangkuo; Xu, Guangchao; Yu, Bao; Jiang, Lan; Luo, Di; Hu, Jianping; Li, Jingyi Jessica; Shi, Hubing

doi:10.1186/s43556-020-00013-0

Cited by 20 publications

(18 citation statements)

References 52 publications

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“…Cell apoptosis assays were performed as previously described [ 45 ]. Cells were stained using the Annexin V Apoptosis Detection Kit (4A Biotech) and analyzed using CytoFLEX (Beckman Coulter).…”

Section: Methodsmentioning

confidence: 99%

Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer

Luo

et al. 2021

Oncogene

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Targeting the KRAS pathway is a promising but challenging approach for colorectal cancer therapy. Despite showing potent efficacy in BRAF-mutated melanoma, MEK inhibitors appeared to be tolerated by colorectal cancer cells due to their intrinsic compensatory signaling. Here, we performed genome-wide CRISPR/Cas9 screening in the presence of MEK inhibitor to identify genes that are synthetically lethal with MEK inhibition in CRC models harboring KRAS mutations. Several genes were identified as potential functional drivers, which were significantly enriched in the GRB7-mediated RTK pathway. Loss-of-function and gain-of-function assays validated that GRB7 potently rendered CRC cells primary resistance to MEK inhibitors through the RTK pathway. Mass spectrum analysis of GRB7 immunoprecipitates revealed that PLK1 was the predominant interacting kinase of GRB7. Inhibition of PLK1 suppressed downstream signaling of RTK, including FAK, STAT3, AKT, and 4EBP1. The combination of PLK1 and MEK inhibitors synergistically inhibited CRC cell proliferation and induced apoptosis in vitro and in vivo. In conclusion, we identified GRB7-PLK1 as a pivotal axis mediating RTKs, resulting in MEK inhibitor tolerance. PLK1 is therefore a promising target for synergizing MEK inhibitors in the clinical treatment of CRC patients harboring KRAS mutations.

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Section: Methodsmentioning

confidence: 99%

Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer

Luo

et al. 2021

Oncogene

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“…Integrins are involved in tumor progression and drug resistance ( Hamidi and Ivaska, 2018 ; Yu et al, 2020 ). As shown by the transcriptomic results of clinically matched samples from patients who had HCC with PVTT, signals of ECM organization and regulation of integrin activation were enriched during PVTT development ( Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

Cancer-Associated Fibroblasts Promote Vascular Invasion of Hepatocellular Carcinoma via Downregulating Decorin-integrin β1 Signaling

Zheng

Wang

et al. 2021

Front. Cell Dev. Biol.

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Hepatocellular carcinoma (HCC) is a common malignancy worldwide, and the high ratio of recurrence and metastasis remains the main cause of its poor prognosis. Vascular invasion of HCC includes microvascular invasion (MVI) and portal vein tumor thrombosis (PVTT) and is regarded as a common roadmap of intrahepatic metastasis in HCC. However, the molecular mechanism underlying vascular invasion of HCC is largely unknown. Here, we analyzed the transcriptomes of primary tumors, PVTT tissues, and tumor tissues with or without MVI. We found that extracellular matrix-related pathways were involved in vascular invasion of HCC and that decorin secreted by cancer-associated fibroblasts was gradually downregulated from normal to tumor tissues and more so in PVTT tissues. We also established that low-level decorin expression is an independent risk factor for MVI and it is associated with a poor prognosis. Decorin downregulated integrin β1 and consequently inhibited HCC cell invasion and migration in vitro. Co-staining DCN and integrin β1 revealed that DCN dynamically regulated integrin β1 protein expression. Integrin β1 knockdown significantly inhibited HCC invasion and migration, and decorin combined with such knockdown synergistically augmented the anti-metastatic effects. Co-IP assay confirmed the direct interaction of decorin with integrin β1. Our findings showed that targeting cancer-associated fibroblast-related decorin is not only a promising strategy for inhibiting HCC vascular invasion and metastasis but also provides insight into the clinical treatment of patients with PVTT.

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“…Drug resistance to targeted drugs including BRAF ( 32 ), MAPK ( 33 ), and MEK ( 34 ) signaling pathways in different cancer types affects patient treatment outcomes. Immunotherapy has been observed to show strong antitumor activity in advanced non-small-cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

A Combination of Biomarkers Predict Response to Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

Jiang

Zhou²,

Huang

2021

Front. Immunol.

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Immune checkpoint blockade (ICB) therapy has provided clinical benefits for patients with advanced non-small-cell lung cancer (NSCLC), but the majority still do not respond. Although a few biomarkers of ICB treatment response have been developed, the predictive power of these biomarkers showed substantial variation across datasets. Therefore, predicting response to ICB therapy remains a challenge. Here, we provided a concise combinatorial strategy for predicting ICB therapy response and constructed the ICB treatment signature (ITS) in lung cancer. The prediction performance of ITS has been validated in an independent ICB treatment cohort of NSCLC, where patients with higher ITS score were significantly associated with longer progression-free survival and better response. And ITS score was more powerful than traditional biomarkers, such as TMB and PD-L1, in predicting the ICB treatment response in NSCLC. In addition, ITS scores still had predictive effects in other cancer data sets, showing strong scalability and robustness. Further research showed that a high ITS score represented comprehensive immune activation characteristics including activated immune cell infiltration, increased mutation load, and TCR diversity. In conclusion, our practice suggested that the combination of biomarkers will lead to a better prediction of ICB treatment prognosis, and the ITS score will provide NSCLC patients with better ICB treatment decisions.

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Integrin-Src-YAP1 signaling mediates the melanoma acquired resistance to MAPK and PI3K/mTOR dual targeted therapy

Cited by 20 publications

References 52 publications

Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer

Genome-wide CRISPR-cas9 knockout screening identifies GRB7 as a driver for MEK inhibitor resistance in KRAS mutant colon cancer

Cancer-Associated Fibroblasts Promote Vascular Invasion of Hepatocellular Carcinoma via Downregulating Decorin-integrin β1 Signaling

A Combination of Biomarkers Predict Response to Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer

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