title: Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.
abstract: Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Adams
authors.affiliation: Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Elamprakash N
authors.initials: EN
authors.lastname: Savariar
authors.affiliation: Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Aguilera
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Crisp
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Karra A
authors.identifier: 0000-0002-8819-8992
authors.initials: KA
authors.lastname: Jones
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Whitney
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.|UC San Diego, Moores Cancer Center, La Jolla, California 92093, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92093, USA.|UC San Diego, Moores Cancer Center, La Jolla, California 92093, USA.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.|UC San Diego, Moores Cancer Center, La Jolla, California 92093, USA.|Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Roger Y
authors.initials: RY
authors.lastname: Tsien
authors.affiliation: Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California 92093, USA.|UC San Diego, Moores Cancer Center, La Jolla, California 92093, USA.
authors.forename: Sunil J
authors.initials: SJ
authors.lastname: Advani
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D062365:Aminobenzoates / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D006801:Humans; D008453:Maytansine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D009842:Oligopeptides / Q000494:pharmacology; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D000068878:Trastuzumab / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D062365:Aminobenzoates; D009842:Oligopeptides; D011838:Radiation-Sensitizing Agents; D050257:Tubulin Modulators; C543533:auristatin; D008453:Maytansine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine