Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies
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
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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Research Article Oncology

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 6

MYD1-72 Fc enhances the effects of chemotherapy in ovarian cancer.

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MYD1-72 Fc enhances the effects of chemotherapy in ovarian cancer. Inhib...
Inhibition of metastasis in the OVCAR8 (A) and SKOV3.ip (B) ovarian cancer models as measured by number of metastases and overall tumor weight. Blue data points represent mice estimated to have over 1,000 metastases, and red outlined data points represent mice with no evidence of disease. Inlaid graphs are expanded views of a subset of the complete data set to highlight differences between treatment groups. The eyes, liver, lungs, and kidneys of mice in the OVCAR8 study (C) were analyzed for histological signs of toxicity. Treatment with MYD1-72 Fc did not result in ocular toxicity; as the integrity of the RPE (arrows) was maintained, no histological abnormalities were present across treatment groups. Representative images are shown from each treatment group. n = 7–10. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 50 μm. Dox, doxorubicin. ANOVA with Tukey-Kramer test was used for comparing multiple treatments to each other.