scholarly journals Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhimin Zhang ◽  
Xiaojuan Lian ◽  
Wei Xie ◽  
Jin Quan ◽  
Maojun Liao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Advanced Lung Cancer ◽  
Tki Resistance ◽  
Geo Dataset ◽  
Epidermal Growth

AbstractResistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.

scholarly journals c-Src Associates with ErbB2 through an Interaction between Catalytic Domains and Confers Enhanced Transforming Potential

2009 ◽  
Vol 29 (21) ◽  
pp. 5858-5871 ◽  
Author(s):  
Richard Marcotte ◽  
Lixin Zhou ◽  
Harold Kim ◽  
Calvin D. Roskelly ◽  
William J. Muller
Keyword(s):  
Kinase Inhibitors ◽  
Catalytic Domain ◽  
Growth Factor Receptor ◽  
Src Tyrosine Kinase ◽  
Increased Sensitivity ◽  
Epidermal Growth ◽  
Egfr Family ◽  
Egfr Mutant

ABSTRACT Previous studies have demonstrated that c-Src tyrosine kinase interacts specifically with ErbB2, but not with other members of the epidermal growth factor receptor (EGFR) family. To identify the site of interaction, we recently used a chimeric EGFR/ErbB2 receptor approach to show that c-Src requires the kinase region of ErbB2 for binding. Here, we demonstrate that retention of a conserved amino acid motif surrounding tyrosine 877 (referred to here as EGFRYHAD) is sufficient to confer binding to c-Src. Surprisingly the association of c-Src was not dependent on its SH2 or SH3 domain or on the phosphorylation or kinase activity of the receptor. We further show that the chimeric EGFRs that contain the Y877 motif are transforming in vitro and in vivo following ligand stimulation. Transformation was also partially dependent on sustained activation of Stat3. Finally, we demonstrate that EGFRs with mutations in the catalytic domain, originally identified in lung cancer and conferring increased sensitivity to gefitinib and erlotinib, two EGFR kinase inhibitors, gained the capacity to bind c-Src. Moreover, transformation by these EGFR mutants was inhibited by Src inhibitors regardless of their sensitivities to gefitinib and erlotinib. These observations have important implications for understanding the molecular basis for resistance to EGFR inhibitors and implicate c-Src as a critical signaling molecule in EGFR mutant-induced transformation.

scholarly journals MicroRNA-16 Restores Sensitivity to Tyrosine Kinase Inhibitors and Outperforms MEK Inhibitors in KRAS-Mutated Non-Small Cell Lung Cancer

2021 ◽  
Vol 22 (24) ◽  
pp. 13357
Author(s):  
Francesca Fanini ◽  
Erika Bandini ◽  
Meropi Plousiou ◽  
Silvia Carloni ◽  
Petra Wise ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Activating Mutations ◽  
Downstream Effectors ◽  
Tki Resistance

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Chemotherapy, the treatment of choice in non-operable cases, achieves a dismal success rate, raising the need for new therapeutic options. In about 25% of NSCLC, the activating mutations of the KRAS oncogene define a subclass that cannot benefit from tyrosine kinase inhibitors (TKIs). The tumor suppressor miR-16 is downregulated in many human cancers, including NSCLC. The main objectives of this study were to evaluate miR-16 treatment to restore the TKI sensitivity and compare its efficacy to MEK inhibitors in KRAS-mutated NSCLC. Methods: We performed in vitro and in vivo studies to investigate whether miR-16 could be exploited to overcome TKI resistance in KRAS-mutated NSCLC. We had three goals: first, to identify the KRAS downstream effectors targeted by mir-16, second, to study the effects of miR-16 restoration on TKI resistance in KRAS-mutated NSCLC both in vitro and in vivo, and finally, to compare miR-16 and the MEK inhibitor selumetinib in reducing KRAS-mutated NSCLC growth in vitro and in vivo. Results: We demonstrated that miR-16 directly targets the three KRAS downstream effectors MAPK3, MAP2K1, and CRAF in NSCLC, restoring the sensitivity to erlotinib in KRAS-mutated NSCLC both in vitro and in vivo. We also provided evidence that the miR-16–erlotinib regimen is more effective than the selumetinib–erlotinib combination in KRAS-mutated NSCLC. Conclusions: Our findings support the biological preclinical rationale for using miR-16 in combination with erlotinib in the treatment of NSCLC with KRAS-activating mutations.

scholarly journals A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
James A Timmons ◽  
Andrew Anighoro ◽  
Robert J Brogan ◽  
Jack Stahl ◽  
Claes Wahlestedt ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Drug Repurposing ◽  
Disease Status ◽  
Gene Signature ◽  
Genome Wide ◽  
Epidermal Growth ◽  
Ir Signature

Insulin resistance (IR) contributes to the pathophysiology of diabetes, dementia, viral infection, and cardiovascular disease. Drug repurposing (DR) may identify treatments for IR; however, barriers include uncertainty whether in vitro transcriptomic assays yield quantitative pharmacological data, or how to optimise assay design to best reflect in vivo human disease. We developed a clinical-based human tissue IR signature by combining lifestyle-mediated treatment responses (>500 human adipose and muscle biopsies) with biomarkers of disease status (fasting IR from >1200 biopsies). The assay identified a chemically diverse set of >130 positively acting compounds, highly enriched in true positives, that targeted 73 proteins regulating IR pathways. Our multi-gene RNA assay score reflected the quantitative pharmacological properties of a set of epidermal growth factor receptor-related tyrosine kinase inhibitors, providing insight into drug target specificity; an observation supported by deep learning-based genome-wide predicted pharmacology. Several drugs identified are suitable for evaluation in patients, particularly those with either acute or severe chronic IR.

scholarly journals UDP-glucose pyrophosphorylase 2, a regulator of glycosylation and glycogen, is essential for pancreatic cancer growth

2020 ◽  
Author(s):  
Andrew L. Wolfe ◽  
Qingwen Zhou ◽  
Eneda Toska ◽  
Jacqueline Galeas ◽  
Angel A. Ku ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Growth Factor Receptor ◽  
Protein Glycosylation ◽  
Epidermal Growth ◽  
Xenograft Models ◽  
Maintenance Metabolism ◽  
Tumor Maintenance

AbstractPancreatic ductal adenocarcinomas (PDACs) have enhanced nutrient uptake requirements and rapid metabolic processing. The enzyme UDP-glucose pyrophosphorylase 2 (UGP2) rests at the convergence of multiple metabolic pathways, however the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an essential role for UGP2 in the maintenance of PDAC growth in both in vitro and in vivo tumor models. Transcription of UGP2 is directly regulated by the YAP/TEAD complex. Loss of UGP2 leads to decreased intracellular glycogen and defects in N-glycosylation targets important for cell growth including epidermal growth factor receptor (EGFR). In murine xenograft models, knockdown of UGP2 halted tumor growth and repressed expression of EGFR. The critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer new avenues of therapy for otherwise intractable PDACs.Impact StatementConvergent findings reveal that UDP-glucose pyrophosphorylase 2 has a central role in growth and metabolism of pancreatic ductal adenocarcinomas, highlighting novel therapeutic possibilities for this deadly cancer.

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