title: Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies.
abstract: The AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression in aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Moreover, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.
authors.forename: Mihalis S
authors.initials: MS
authors.lastname: Kariolis
authors.forename: Yu Rebecca
authors.initials: YR
authors.lastname: Miao
authors.forename: Anh
authors.initials: A
authors.lastname: Diep
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Nash
authors.forename: Monica M
authors.initials: MM
authors.lastname: Olcina
authors.forename: Dadi
authors.initials: D
authors.lastname: Jiang
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Jones
authors.forename: Shiven
authors.initials: S
authors.lastname: Kapur
authors.forename: Irimpan I
authors.initials: II
authors.lastname: Mathews
authors.forename: Albert C
authors.initials: AC
authors.lastname: Koong
authors.forename: Erinn B
authors.initials: EB
authors.lastname: Rankin
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Cochran
authors.forename: Amato J
authors.initials: AJ
authors.lastname: Giaccia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006657:Histones; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D051135:Rad51 Recombinase; D020794:Receptor Protein-Tyrosine Kinases; D000071857:Tumor Suppressor p53-Binding Protein 1; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C468783:H2AX protein, human; C498301:TP53BP1 protein, human; C495153:RAD51 protein, human