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Title: Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies

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. But, 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. 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. Furthermore, 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:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [2] ;  [3] ;  [1] ;  [1] ;  [2] ;  [1]
  1. Stanford Univ. of Medicine, CA (United States). Dept. of Radiation Oncology
  2. Stanford Univ., CA (United States). Dept. of Bioengineering
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource
Publication Date:
Grant/Contract Number:
AC02-76SF00515
Type:
Accepted Manuscript
Journal Name:
Journal of Clinical Investigation
Additional Journal Information:
Journal Volume: 127; Journal Issue: 1; Journal ID: ISSN 0021-9738
Research Org:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES
OSTI Identifier:
1361055

Kariolis, Mihalis S., Miao, Yu Rebecca, Diep, Anh, Nash, Shannon E., Olcina, Monica M., Jiang, Dadi, Jones, Douglas S., Kapur, Shiven, Mathews, Irimpan I., Koong, Albert C., Rankin, Erinn B., Cochran, Jennifer R., and Giaccia, Amato J.. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. United States: N. p., Web. doi:10.1172/JCI85610.
Kariolis, Mihalis S., Miao, Yu Rebecca, Diep, Anh, Nash, Shannon E., Olcina, Monica M., Jiang, Dadi, Jones, Douglas S., Kapur, Shiven, Mathews, Irimpan I., Koong, Albert C., Rankin, Erinn B., Cochran, Jennifer R., & Giaccia, Amato J.. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies. United States. doi:10.1172/JCI85610.
Kariolis, Mihalis S., Miao, Yu Rebecca, Diep, Anh, Nash, Shannon E., Olcina, Monica M., Jiang, Dadi, Jones, Douglas S., Kapur, Shiven, Mathews, Irimpan I., Koong, Albert C., Rankin, Erinn B., Cochran, Jennifer R., and Giaccia, Amato J.. 2016. "Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies". United States. doi:10.1172/JCI85610. https://www.osti.gov/servlets/purl/1361055.
@article{osti_1361055,
title = {Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies},
author = {Kariolis, Mihalis S. and Miao, Yu Rebecca and Diep, Anh and Nash, Shannon E. and Olcina, Monica M. and Jiang, Dadi and Jones, Douglas S. and Kapur, Shiven and Mathews, Irimpan I. and Koong, Albert C. and Rankin, Erinn B. and Cochran, Jennifer R. and Giaccia, Amato J.},
abstractNote = {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. But, 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. 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. Furthermore, 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.},
doi = {10.1172/JCI85610},
journal = {Journal of Clinical Investigation},
number = 1,
volume = 127,
place = {United States},
year = {2016},
month = {11}
}