Bioinformatics-driven discovery of rational combination for overcoming EGFR-mutant lung cancer resistance to EGFR therapy

Kim, Jihye; Vasu, Vihas T.; Mishra, Rangnath; Singleton, Katherine R.; Yoo, Minjae; Leach, Sonia M.; Farias-Hesson, Eveline; Mason, Robert J.; Kang, Jaewoo; Ramamoorthy, Preveen; Kern, Jeffrey A.; Heasley, Lynn E.; Finigan, James H.; Tan, Aik Choon

doi:10.1093/bioinformatics/btu323

Cited by 21 publications

(24 citation statements)

References 33 publications

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“…The counts of gene hits were significantly lower from Vehicle to IC 20 and IC 80 (E-value < 2), maximum difference is Vehicle to IC 20 among all possible combinations, and no significant changes from IC 20 to IC 50 and IC 50 to IC 80 . This analysis approach is similar to our previously published research (76). …”

Section: Methodsmentioning

confidence: 65%

Coupling an EML4-ALK–centric interactome with RNA interference identifies sensitizers to ALK inhibitors

et al. 2016

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Patients with lung cancers harboring anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK kinase inhibitors but acquired resistance inevitably arises. A better understanding of proximal ALK signaling mechanisms may identify sensitizers to ALK inhibitors that disrupt the balance between pro-survival and pro-apoptotic effector signals. Using affinity purification coupled with mass spectrometry in an ALK fusion lung cancer cell line (H3122), we generated an ALK signaling network and investigated signaling activity using tyrosine phosphoproteomics. We identified a network of 464 proteins composed of subnetworks with differential response to ALK inhibitors. A small hairpin RNA screen targeting 407 proteins in this network revealed 64 and 9 proteins whose loss sensitized cells to crizotinib and alectinib, respectively. Among these, knocking down fibroblast growth factor receptor substrate 2 (FRS2) or coiled-coil and C2 domain-containing protein 1A (CC2D1A, both scaffolding proteins, sensitized multiple ALK fusion cell lines to the ALK inhibitors crizotinib and alectinib. Collectively, our data provides a resource that enhances our understanding of signaling and drug resistance networks consequent to ALK fusions, and identifies potential targets to improve the efficacy of ALK inhibitors in patients.

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Section: Methodsmentioning

confidence: 65%

Coupling an EML4-ALK–centric interactome with RNA interference identifies sensitizers to ALK inhibitors

et al. 2016

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“…We recently developed and implemented K-Map that systematically connects a kinase profile with a reference kinase inhibitor database and predicts the most effective inhibitor for a queried kinase profile [ 26 , 27 ]. The K-Map consists of three key components: (1) a reference database that contains a set of kinase inhibitors profiles; (2) a query signature; and (3) a pattern matching algorithm or similarity metric defined between a query signature and a reference kinase inhibitor profile to quantify the connection (or similarity) between the interactions of kinases and inhibitors.…”

Section: Methodsmentioning

confidence: 99%

“…We employed our recently developed Kinase Addiction Ranker (KAR) to integrate these data sourcesto dissect kinase dependency in TNBC cell lines[ 25 ]. We then used the kinase dependency predicted by KAR to query K-Map [ 26 , 27 ]for connecting compounds with kinases for individual TNBC lines. For validation, we performed literature search on published experimental data and tested K-Map predictionsin cell lines.…”

Section: Introductionmentioning

confidence: 99%

An integrated bioinformatics analysis to dissect kinase dependency in triple negative breast cancer

et al. 2015

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BackgroundTriple-Negative Breast Cancer (TNBC) is an aggressive disease with a poor prognosis. Clinically, TNBC patients have limited treatment options besides chemotherapy. The goal of this study was to determine the kinase dependency in TNBC cell lines and to predict compounds that could inhibit these kinases using integrative bioinformatics analysis.ResultsWe integrated publicly available gene expression data, high-throughput pharmacological profiling data, and quantitative in vitro kinase binding data to determine the kinase dependency in 12 TNBC cell lines. We employed Kinase Addiction Ranker (KAR), a novel bioinformatics approach, which integrated these data sources to dissect kinase dependency in TNBC cell lines. We then used the kinase dependency predicted by KAR for each TNBC cell line to query K-Map for compounds targeting these kinases. Wevalidated our predictions using published and new experimental data.ConclusionsIn summary, we implemented an integrative bioinformatics analysis that determines kinase dependency in TNBC. Our analysis revealed candidate kinases as potential targets in TNBC for further pharmacological and biological studies.

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“…What is more, PIK3CA mutation, [ 12 ] ERBB2 amplification, [ 13 ] HGF overexpression, [ 14 ] AXL activation, [ 15 ] epithelial-mesenchymal transition, and pathology type transformation, especially adenocarcinoma transformation into small cell lung cancer, have also been reported as causes of secondary resistance to EGFR-TKIs. [ 16 – 18 ]…”

Section: Introductionmentioning

confidence: 99%

Microwave ablation combined with EGFR-TKIs versus only EGFR-TKIs in advanced NSCLC patients with EGFR-sensitive mutations

Wei

Yang

et al. 2017

Oncotarget

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We conducted this retrospective study to investigate whether microwave ablation (MWA) of primary tumor sites plus epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) could improve survival in advanced non small cell lung cancer (NSCLC) with EGFR mutations. MWA was conducted at the primary tumor sites, followed by EGFR-TKIs in the MWA plus EGFR-TKIs group. EGFR-TKIs were administered until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS) and objective response rate (ORR). A total of 58 patients were recruited, including 34 in the MWA plus EGFR-TKIs group and 24 in the EGFR-TKIs group. No significant difference in ORR was observed with MWA treatment (61.8% vs. 45.8%, p = 0.230). Patients treated with MWA plus EGFR-TKIs failed to show superior survival in either PFS (13.2 months vs. 11.6 months, p = 0.640) or OS (39.8 months vs. 20.4 months, p = 0.288). MWA was not an independent prognostic factor for PFS or OS. MWA of primary tumor sites plus EGFR-TKIs demonstrated no survival advantage compared with EGFR-TKIs alone in advanced NSCLC patients with EGFR sensitive mutations. MWA should not be recommended for unselected patients with EGFR-sensitive mutations.

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Bioinformatics-driven discovery of rational combination for overcoming EGFR-mutant lung cancer resistance to EGFR therapy

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 21 publications

References 33 publications

Coupling an EML4-ALK–centric interactome with RNA interference identifies sensitizers to ALK inhibitors

Coupling an EML4-ALK–centric interactome with RNA interference identifies sensitizers to ALK inhibitors

An integrated bioinformatics analysis to dissect kinase dependency in triple negative breast cancer

Microwave ablation combined with EGFR-TKIs versus only EGFR-TKIs in advanced NSCLC patients with EGFR-sensitive mutations

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