ArticleOncotarget2018
Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer.
Article in Oncotarget, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- A comprehensive pharmacological survey across heterogeneous patient-derived glioblastoma stem cell models.iScience · 2026Article
- Hyaluronan: An Architect and Integrator for Cancer and Neural Diseases.International journal of molecular sciences · 2025Review
- DUSP1 Promotes Osimertinib Drug-Tolerant Persistence by Inhibiting MAPK/ERK Signaling in Non-small Cell Lung Cancer.Molecular biotechnology · 2025Article
- The IGF2BP1 oncogene is a druggable mNAR cancer · 2025Article
- Molecular pathways in reproductive cancers: a focus on prostate and ovarian cancer.Cancer cell international · 2025Review
- Dual Drug Repurposing: The Example of Saracatinib.International journal of molecular sciences · 2024Review
- Disabled-2 (International journal of molecular sciences · 2022Review
- Article
- Pathway profiling of a novel SRC inhibitor, AZD0424, in combination with MEK inhibitors for cancer treatment.Molecular oncology · 2022Article
- SAR Probing of KX2-391 Provided Analogues With Juxtaposed Activity Profile Against Major Oncogenic Kinases.Frontiers in oncology · 2022Article
- Review
- Differential gene expression identifies a transcriptional regulatory network involving ER-alpha and PITX1 in invasive epithelial ovarian cancer.BMC cancer · 2021Article
- MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2021Review
- IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer.RNA biology · 2021Article
- A Rab escort protein regulates the MAPK pathway that controls filamentous growth in yeast.Scientific reports · 2020Article
- Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy.Journal of translational medicine · 2020Article
- Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer.Cancers · 2020Article
- LncRNA HEIH Enhances Paclitaxel-Tolerance of Endometrial Cancer Cells via Activation of MAPK Signaling Pathway.Pathology oncology research : POR · 2020Article
- Novel Contribution of Secreted Amyloid-β Precursor Protein to White Matter Brain Enlargement in Autism Spectrum Disorder.Frontiers in psychiatry · 2019Review
- Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance.Cancers · 2018Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.