PHLDA1 Mediates Drug Resistance in Receptor Tyrosine Kinase-Driven Cancer
نویسندگان
چکیده
Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2+ breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.
منابع مشابه
Modulation of ErbB2 Blockade in ErbB2-Positive Cancers: The Role of ErbB2 Mutations and PHLDA1
We set out to study the key effectors of resistance and sensitivity to ErbB2 tyrosine kinase inhibitors, such as lapatinib in ErbB2-positive breast and lung cancers. A cell-based in vitro site-directed mutagenesis lapatinib resistance model identified several mutations, including the gatekeeper ErbB2 mutation ErbB2-T798I, as mediating resistance. ErbB2-T798I engineered cell models indeed show r...
متن کاملFMS-like Tyrosine Kinase-3 Mutation in a Child with Standard-risk ALL and Normal Karyotype
FMS-like tyrosine kinase-3 is a receptor tyrosine kinase expressed by immature hematopoietic cells and is important for the normal development of stem cells and the immune system. Mutations of FMS-like tyrosine kinase-3 have been detected in about 30% of patients with acute myelogenous leukemia and a small number of patients with acute lymphoblastic leukemia. The FMS-like tyrosine kinase-3 muta...
متن کاملMolecular Docking Based on Virtual Screening, Molecular Dynamics and Atoms in Molecules Studies to Identify the Potential Human Epidermal Receptor 2 Intracellular Domain Inhibitors
Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Overexpression of HER2 usually causes malignant transformation of cells and is responsible for the breast cancer. In this work, the virtual screening, molecular docking, quantum mechanics and molecular dynamics methods were employed to study protein–ligand ...
متن کاملTherapeutic Discovery Cigarette Smoke Induces Aberrant EGF Receptor Activation That Mediates Lung Cancer Development and Resistance to Tyrosine Kinase Inhibitors
TheEGF receptor (EGFR) and its downstreamsignaling are implicated in lung cancer development. Therefore, much effort was spent in developing specific tyrosine kinase inhibitors (TKI) that bind to the EGFRATP-pocket, blocking EGFR phosphorylation/signaling. Clinical use of TKIs is effective in a subset of lung cancers with mutations in theEGFRkinasedomain, rendering the receptorhighly susceptibl...
متن کاملReceptor Tyrosine Kinase Inhibitory Activities and Molecular Docking Studies of Some Pyrrolo[2,3-d]pyrimidine Derivatives
In this study, we aimed to determine VEGFR-2, EGFR and PDGFR-β tyrosine kinase inhibitory activities of some pyrrolo[2,3-d]pyrimidine derivatives previously synthesized and showed potent cytotoxic and apoptotic effects against several cancer cell lines by our group and to evaluate the relationships between inhibitory activities and binding properties of the active compounds by molecular docking...
متن کامل