title: Targeted nanoconjugate co-delivering siRNA and tyrosine kinase inhibitor to KRAS mutant NSCLC dissociates GAB1-SHP2 post oncogene knockdown.
abstract: A tri-block nanoparticle (TBN) comprising of an enzymatically cleavable porous gelatin nanocore encapsulated with gefitinib (tyrosine kinase inhibitor (TKI)) and surface functionalized with cetuximab-siRNA conjugate has been synthesized. Targeted delivery of siRNA to undruggable KRAS mutated non-small cell lung cancer cells would sensitize the cells to TKI drugs and offers an efficient therapy for treating cancer; however, efficient delivery of siRNA and releasing it in cytoplasm remains a major challenge. We have shown TBN can efficiently deliver siRNA to cytoplasm of KRAS mutant H23 Non-Small Cell Lung Cancer (NSCLC) cells for oncogene knockdown; subsequently, sensitizing it to TKI. In the absence of TKI, the nanoparticle showed minimal toxicity suggesting that the cells adapt a parallel GAB1 mediated survival pathway. In H23 cells, activated ERK results in phosphorylation of GAB1 on serine and threonine residues to form GAB1-p85 PI3K complex. In the absence of TKI, knocking down the oncogene dephosphorylated ERK, and negated the complex formation. This event led to tyrosine phosphorylation at Tyr627 domain of GAB1 that regulated EGFR signaling by recruiting SHP2. In the presence of TKI, GAB1-SHP2 dissociation occurs, leading to cell death. The outcome of this study provides a promising platform for treating NSCLC patients harboring KRAS mutation.
authors.affiliation: Department of Radiology, Medical Sciences Building, University of Missouri, Columbia, MO 65212, USA.
authors.forename: R
authors.initials: R
authors.lastname: Srikar
authors.affiliation: Department of Bioengineering, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Suresh
authors.affiliation: Department of Radiology, Medical Sciences Building, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Zambre
authors.affiliation: Department of Pathology, Medical Sciences Building, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Notre Dame Integrated Imaging Facility, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Chapman
authors.affiliation: Notre Dame Integrated Imaging Facility, University of Notre Dame, Notre Dame, IN 46556, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Leevy
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.|Institute of Clinical and Translational Science, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Anandhi
authors.initials: A
authors.lastname: Upendran
authors.affiliation: Department of Radiology, Medical Sciences Building, University of Missouri, Columbia, MO 65212, USA.|Department of Bioengineering, University of Missouri, Columbia, MO 65212, USA.|International Center for Nano/Micro Systems and Nanotechnology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Raghuraman
authors.initials: R
authors.lastname: Kannan
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000737:chemistry / Q000494:pharmacology*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems; D000077156:Gefitinib; D005780:Gelatin / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D058726:Nanoconjugates / Q000737:chemistry / Q000648:ultrastructure; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C098587:GAB1 protein, human; C117307:KRAS protein, human; D058726:Nanoconjugates; D011799:Quinazolines; D034741:RNA, Small Interfering; D005780:Gelatin; D058543:Class Ia Phosphatidylinositol 3-Kinase; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D000077156:Gefitinib