Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies
Mihalis S. Kariolis, … , Jennifer R. Cochran, Amato J. Giaccia
Mihalis S. Kariolis, … , Jennifer R. Cochran, Amato J. Giaccia
Published January 3, 2017; First published November 28, 2016
Citation Information: J Clin Invest. 2017;127(1):183-198. https://doi.org/10.1172/JCI85610.
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Categories: Research Article Oncology Therapeutics

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

Mihalis S. Kariolis, Yu Rebecca Miao, Anh Diep, Shannon E. Nash, Monica M. Olcina, Dadi Jiang, Douglas S. Jones II, Shiven Kapur, Irimpan I. Mathews, Albert C. Koong, Erinn B. Rankin, Jennifer R. Cochran, Amato J. Giaccia

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Figure 5

Treatment with MYD1-72 induces DNA-damage response during cell S phase.

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Treatment with MYD1-72 induces DNA-damage response during cell S phase. ...
(A) Immunofluorescence staining of γH2AX foci formation in ovarian cancer cells treated with MYD1-72 Fc alone or in combination with doxorubicin. n = 7-9. (B) Western blot analysis was carried out to examine changes in the phosphorylation of ATM, ATR, CHK1, CHK2, and RPA32 in ovarian cancer cells cultured in low serum (0.1% FBS) after treatment with MYD1-72 Fc. (C) Representative images of EdU- and γH2AX-positive cells and (D) quantification of γH2AX-positive cells in MYD1-72 Fc vs. control treated cells. The differences in the number of S phase cells (EdU positive) between control and MYD1-72 Fc–treated groups are shown. No click refers to the negative control for EdU staining (E). The percentage of γH2AX-positive cells that are in S phase (EdU positive) between control and MYD1-72 Fc–treated group is shown in F. n = 3. *P < 0.05; ****P < 0.0001. Scale bars: 15 μm. ANOVA with Tukey-Kramer test was used for comparing multiple treatments to each other, and Student’s t test was used for comparing single treatments to the control.