title: HER2+ breast cancer therapy: by CPP-ZFN mediated targeting of mTOR?
abstract: A significant fraction of HER2+ patients develop resistance to available therapies such as trastuzumab. The acquired resistance is primarily due to hyper activation of HER2 downstream PI3K/Akt/mTOR signalling pathway. Hence, identification of inhibitors of components of this pathway, particularly mTOR, is an area of intense investigation. Interestingly, mTOR specific inhibitors (rapamycin/rapalogs) have been tested and shown to potentiate the effect of HER2 inhibitors. However, the use of mTOR inhibitors will also be associated with the limitations inherently linked with extensive use of anticancer drugs e.g., toxicity and acquired drug resistance. Hereby, we hypothesize development of an alternative novel molecular therapeutic intervention based on cell penetrating peptide (CPP), a highly efficient carrier, conjugated to zinc finger nuclease (ZFN), a precise molecular scissor. The use of HER2 specific CPP conjugated to mTOR specific ZFN, will make the mTOR locus non-functional and inhibit the PI3K/Akt/mTOR pathway, essential for growth and proliferation of cancerous cells. With the availability of HER21 cancerous cell specific CPP and proved applications of ZFN in targeted genome engineering of over 11 species, the prospects of success of CPP-ZFN anti-cancer therapy are very high.
authors.affiliation: School of Biotechnology, Gautam Buddha University, Greater NOIDA, Gautam Budh Nagar-201310, India. rpuria@gbu.ac.in
authors.forename: Rekha
authors.initials: R
authors.lastname: Puria
authors.forename: Shakti
authors.initials: S
authors.lastname: Sahi
authors.forename: Vikrant
authors.initials: V
authors.lastname: Nain
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D057846:Cell-Penetrating Peptides / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D003851:Deoxyribonucleases / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D018390:Gene Targeting; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D016335:Zinc Fingers
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004247:DNA; D003851:Deoxyribonucleases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C546842:MTOR protein, human; C508053:ERBB2 protein, human