Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC)

Karachaliou, Niki; Cardona, Andrés Felipe; Bracht, Jillian Wilhelmina Paulina; Aldeguer, Erika; Drozdowskyj, Ana; Fernández-Bruno, Manuel; Chaib, Imane; Berenguer, Jordi; Santarpía, Mariacarmela; Ito, Masaoki; Codony-Servat, Jordi; Rosell, Rafael

doi:10.1016/j.ebiom.2018.11.036

Cited by 39 publications

(39 citation statements)

References 36 publications

(65 reference statements)

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“…To our positive surprise, the double combination reversed the osimertinib-induced STAT3 phosphorylation in both cell lines, and diminished paxillin and Src phosphorylation in PC9 and H1975 cells, respectively [ Figure 3B, right panel]. Overall these data reconfirm our previous findings that, even in oncogene addicted EGFR-mutation positive cancer cells, single EGFR TKIs are insufficient [6][7][8]34] . Concomitant PIM-1 inhibition may reverse some of the deleterious effects of osimertinib on the activation of oncogenic signaling pathways.…”

Section: Combination Of Osimertinib Plus a Pim Inhibitor In Egfr-mutasupporting

confidence: 88%

“…However, ultimately resistance mechanisms take over and treatment options are not indefinite. Furthermore, about 20% of EGFR-mutation positive patients have intrinsic resistance to EGFR TKIs [8,34] , indicating that molecularly targeted therapy is not a one-size-fits-all approach. Therefore, defining biomarkers of resistance and designing a truly personalized therapy is of great relevance.…”

Section: Discussionmentioning

confidence: 99%

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PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

Bracht¹,

Karachaliou²,

Berenguer³

et al. 2019

JCMT

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Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC. Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines. Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation. Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.

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Section: Combination Of Osimertinib Plus a Pim Inhibitor In Egfr-mutasupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

Bracht¹,

Karachaliou²,

Berenguer³

et al. 2019

JCMT

Self Cite

View full text Add to dashboard Cite

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“…Osteoinductive factor (OGN) has been demonstrated to reduce cell proliferation and inhibit invasion in colorectal cancer 44 . A recent study reported that integrin-linked kinase (ILK) could promote www.nature.com/scientificreports/ cell proliferation and migration in non-small-cell lung cancer 45 . Moreover, transforming growth factor (TGF)-B3 has been widely accepted as a crucial mediator of tumour progression [46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

Identification of immune-related genes as prognostic factors in bladder cancer

Zhu

Wang²,

et al. 2020

Sci Rep

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Bladder cancer is one of the most common cancers worldwide. The immune response and immune cell infiltration play crucial roles in tumour progression. Immunotherapy has delivered breakthrough achievements in the past decade in bladder cancer. Differentially expressed genes and immune-related genes (DEIRGs) were identified by using the edgeR package. Gene ontology annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for functional enrichment analysis of DEIRGs. Survival-associated IRGs were identified by univariate Cox regression analysis. A prognostic model was established by univariate COX regression analysis, and verified by a validation prognostic model based on the GEO database. Patients were divided into high-risk and low-risk groups based on the median risk score value for immune cell infiltration and clinicopathological analyses. A regulatory network of survival-associated IRGs and potential transcription factors was constructed to investigate the potential regulatory mechanisms of survival-associated IRGs. Nomogram and ROC curve to verify the accuracy of the model. Quantitative real-time PCR was performed to validate the expression of relevant key genes in the prognostic model. A total of 259 differentially expressed IRGs were identified in the present study. KEGG pathway analysis of IRGs showed that the “cytokine-cytokine receptor interaction” pathway was the most significantly enriched pathway. Thirteen survival-associated IRGs were selected to establish a prognostic index for bladder cancer. In both TCGA prognostic model and GEO validation model, patients with high riskscore had worse prognosis compared to low riskscore group. A high infiltration level of macrophages was observed in high-risk patients. OGN, ELN, ANXA6, ILK and TGFB3 were identified as hub survival-associated IRGs in the network. EBF1, WWTR1, GATA6, MYH11, and MEF2C were involved in the transcriptional regulation of these survival-associated hub IRGs. The present study identified several survival-associated IRGs of clinical significance and established a prognostic index for bladder cancer outcome evaluation for the first time.

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“…In cancer, ILK and adaptor proteins regulate interactions between tumor cells and the extracellular environment to activate signaling pathways that promote cell proliferation, migration, and epithelial-to-mesenchymal transition . In several human tumors, including non-small cell lung cancer, high ILK and LIMS1 expression correlates with increased disease progression [31][32] and in EGFR-mutant patients, correlates with significantly worse progression-free survival after treatment with EGFR inhibitors 33 . Consistent with a role for ILK in mediating EGFR-TKI resistance,…”

Section: Integrative Analysis Of Isogenic Crispr Screen Data Reveals mentioning

confidence: 99%

An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer

Vichas

Nkinsi

Riley

et al. 2020

Preprint

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ABSTRACTAdvances in precision oncology have transformed cancer therapy from broadly-applied cytotoxic therapy to personalized treatments based on each tumor’s unique molecular alterations. Here we investigate the oncogene-specific dependencies conferred by lung cancer driver variants of KRAS, EGFR, and RIT1. Integrative analysis of genome-wide CRISPR screens in isogenic cell lines identified shared and unique vulnerabilities of each oncogene. The non-identical landscape of dependencies underscores the importance of genotype-guided therapies to maximize tumor responses. Combining genetic screening data with small molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. This sensitivity may be related to a novel role of RIT1 in mitosis; we find that oncogenic RIT1M90I alters mitotic timing via weakening of the spindle assembly checkpoint. In addition, we uncovered a specific cooperation of mutant RIT1 with loss of Hippo pathway genes. In human lung cancer, RIT1 mutations and amplifications frequently co-occur with loss of Hippo pathway gene expression. These results provide the first genome-wide atlas of oncogenic RIT1-cooperating factors and genetic dependencies and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.

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Integrin-linked kinase (ILK) and src homology 2 domain-containing phosphatase 2 (SHP2): Novel targets in EGFR-mutation positive non-small cell lung cancer (NSCLC)

Cited by 39 publications

References 36 publications

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

Identification of immune-related genes as prognostic factors in bladder cancer

An integrative oncogene-dependency map identifies unique vulnerabilities of oncogenic EGFR, KRAS, and RIT1 in lung cancer

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