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

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.

doi:10.1172/JCI85610

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

Journal Article · Mon Nov 28 00:00:00 EST 2016 · Journal of Clinical Investigation

DOI:https://doi.org/10.1172/JCI85610· OSTI ID:1361055

Kariolis, Mihalis S. ^[1]; Miao, Yu Rebecca ^[1]; Diep, Anh ^[1]; Nash, Shannon E. ^[1]; Olcina, Monica M. ^[1]; Jiang, Dadi ^[1]; Jones, Douglas S. ^[2]; Kapur, Shiven ^[2]; Mathews, Irimpan I. ^[3]; Koong, Albert C. ^[1]; Rankin, Erinn B. ^[1]; Cochran, Jennifer R. ^[2]; Giaccia, Amato J. ^[1]

Stanford Univ. of Medicine, CA (United States). Dept. of Radiation Oncology
Stanford Univ., CA (United States). Dept. of Bioengineering
SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource

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.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1361055

Journal Information:: Journal of Clinical Investigation, Vol. 127, Issue 1; ISSN 0021-9738

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 67 works

Citation information provided by
Web of Science

References (45)

Antibody therapy of cancer Scott, Andrew M.; Wolchok, Jedd D.; Old, Lloyd J. Nature Reviews Cancer, Vol. 12, Issue 4 https://doi.org/10.1038/nrc3236	journal	March 2012
A small molecule–kinase interaction map for clinical kinase inhibitors Fabian, Miles A.; Biggs, William H.; Treiber, Daniel K. Nature Biotechnology, Vol. 23, Issue 3 https://doi.org/10.1038/nbt1068	journal	February 2005
Tumor metastasis: moving new biological insights into the clinic Wan, Liling; Pantel, Klaus; Kang, Yibin Nature Medicine, Vol. 19, Issue 11 https://doi.org/10.1038/nm.3391	journal	November 2013
Immunobiology of the TAM receptors Lemke, Greg; Rothlin, Carla V. Nature Reviews Immunology, Vol. 8, Issue 5 https://doi.org/10.1038/nri2303	journal	May 2008
axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. O'Bryan, J. P.; Frye, R. A.; Cogswell, P. C. Molecular and Cellular Biology, Vol. 11, Issue 10 https://doi.org/10.1128/MCB.11.10.5016	journal	October 1991
Axl as a potential therapeutic target in cancer: role of Axl in tumor growth, metastasis and angiogenesis Li, Y.; Ye, X.; Tan, C. Oncogene, Vol. 28, Issue 39 https://doi.org/10.1038/onc.2009.212	journal	July 2009
AXL Is an Essential Factor and Therapeutic Target for Metastatic Ovarian Cancer Rankin, E. B.; Fuh, K. C.; Taylor, T. E. Cancer Research, Vol. 70, Issue 19 https://doi.org/10.1158/0008-5472.CAN-10-1267	journal	September 2010
Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival Vajkoczy, P.; Knyazev, P.; Kunkel, A. Proceedings of the National Academy of Sciences, Vol. 103, Issue 15 https://doi.org/10.1073/pnas.0510923103	journal	April 2006
Axl and prostasin are biomarkers for prognosis of ovarian adenocarcinoma Chen, Pu-xiang; Li, Qiao-yan; Yang, Zhulin Annals of Diagnostic Pathology, Vol. 17, Issue 5 https://doi.org/10.1016/j.anndiagpath.2013.01.005	journal	October 2013
Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival Gjerdrum, C.; Tiron, C.; Hoiby, T. Proceedings of the National Academy of Sciences, Vol. 107, Issue 3 https://doi.org/10.1073/pnas.0909333107	journal	December 2009
Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer Zhang, Zhenfeng; Lee, Jae Cheol; Lin, Luping Nature Genetics, Vol. 44, Issue 8 https://doi.org/10.1038/ng.2330	journal	July 2012
ABL Regulation by AXL Promotes Cisplatin Resistance in Esophageal Cancer Hong, Jun; Peng, DunFa; Chen, Zheng Cancer Research, Vol. 73, Issue 1 https://doi.org/10.1158/0008-5472.CAN-12-3151	journal	November 2012
Tyro-3 family receptors are essential regulators of mammalian spermatogenesis Lu, Qingxian; Gore, Martin; Zhang, Qing Nature, Vol. 398, Issue 6729 https://doi.org/10.1038/19554	journal	April 1999
Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl, Sky, and Mer Receptor Tyrosine Kinases Nagata, Kyoko; Ohashi, Kazumasa; Nakano, Toru Journal of Biological Chemistry, Vol. 271, Issue 47 https://doi.org/10.1074/jbc.271.47.30022	journal	November 1996
Axl receptor tyrosine kinase stimulated by the vitamin K-dependent protein encoded by growth-arrest-specific gene 6 Varnum, Brian C.; Young, Cynthia; Elliott, Gary Nature, Vol. 373, Issue 6515 https://doi.org/10.1038/373623a0	journal	February 1995
An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis Kariolis, Mihalis S.; Miao, Yu Rebecca; Jones, Douglas S. Nature Chemical Biology, Vol. 10, Issue 11 https://doi.org/10.1038/nchembio.1636	journal	September 2014
Cytokine traps: multi-component, high-affinity blockers of cytokine action Economides, Aris N.; Carpenter, Laura Rocco; Rudge, John S. Nature Medicine, Vol. 9, Issue 1 https://doi.org/10.1038/nm811	journal	December 2002
Beyond antibodies: using biological principles to guide the development of next-generation protein therapeutics Kariolis, Mihalis S.; Kapur, Shiven; Cochran, Jennifer R. Current Opinion in Biotechnology, Vol. 24, Issue 6 https://doi.org/10.1016/j.copbio.2013.03.017	journal	December 2013
A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity Peppel, K. Journal of Experimental Medicine, Vol. 174, Issue 6 https://doi.org/10.1084/jem.174.6.1483	journal	December 1991
VEGF-Trap: A VEGF blocker with potent antitumor effects Holash, J.; Davis, S.; Papadopoulos, N. Proceedings of the National Academy of Sciences, Vol. 99, Issue 17 https://doi.org/10.1073/pnas.172398299	journal	August 2002
Structural basis for Gas6–Axl signalling Sasaki, Takako; Knyazev, Pjotr G.; Clout, Naomi J. The EMBO Journal, Vol. 25, Issue 1 https://doi.org/10.1038/sj.emboj.7600912	journal	December 2005
Isolating and engineering human antibodies using yeast surface display Chao, Ginger; Lau, Wai L.; Hackel, Benjamin J. Nature Protocols, Vol. 1, Issue 2 https://doi.org/10.1038/nprot.2006.94	journal	July 2006
Inhibition of the receptor tyrosine kinase Axl impedes activation of the FLT3 internal tandem duplication in human acute myeloid leukemia: implications for Axl as a potential therapeutic target Park, Il-Kyoo; Mishra, Anjali; Chandler, Jason Blood, Vol. 121, Issue 11 https://doi.org/10.1182/blood-2012-07-444018	journal	March 2013
Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis Thiede, Christian; Steudel, Christine; Mohr, Brigitte Blood, Vol. 99, Issue 12 https://doi.org/10.1182/blood.V99.12.4326	journal	June 2002
R428, a Selective Small Molecule Inhibitor of Axl Kinase, Blocks Tumor Spread and Prolongs Survival in Models of Metastatic Breast Cancer Holland, S. J.; Pan, A.; Franci, C. Cancer Research, Vol. 70, Issue 4 https://doi.org/10.1158/0008-5472.CAN-09-2997	journal	February 2010
Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks Kataoka, Yu; Mukohara, Toru; Tomioka, Hideo Investigational New Drugs, Vol. 30, Issue 4 https://doi.org/10.1007/s10637-011-9699-0	journal	June 2011
Foretinib (GSK1363089), an Orally Available Multikinase Inhibitor of c-Met and VEGFR-2, Blocks Proliferation, Induces Anoikis, and Impairs Ovarian Cancer Metastasis Zillhardt, M.; Park, S. -M.; Romero, I. L. Clinical Cancer Research, Vol. 17, Issue 12 https://doi.org/10.1158/1078-0432.CCR-10-3387	journal	May 2011
Axl is essential for VEGF-A-dependent activation of PI3K/Akt: VEGF-dependent activation of PI3K/Akt requires Axl Ruan, Guo-Xiang; Kazlauskas, Andrius The EMBO Journal, Vol. 31, Issue 7 https://doi.org/10.1038/emboj.2012.21	journal	February 2012
Axl receptor activation mediates laminar shear stress anti-apoptotic effects in human endothelial cells Darcangelo, D.; Ambrosino, V.; Giannuzzo, M. Cardiovascular Research, Vol. 71, Issue 4 https://doi.org/10.1016/j.cardiores.2006.06.002	journal	September 2006
Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET Rankin, Erinn B.; Fuh, Katherine C.; Castellini, Laura Proceedings of the National Academy of Sciences, Vol. 111, Issue 37 https://doi.org/10.1073/pnas.1404848111	journal	September 2014
AXL Mediates Resistance to PI3Kα Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas Elkabets, Moshe; Pazarentzos, Evangelos; Juric, Dejan Cancer Cell, Vol. 27, Issue 4 https://doi.org/10.1016/j.ccell.2015.03.010	journal	April 2015
Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer Bowtell, David D.; Böhm, Steffen; Ahmed, Ahmed A. Nature Reviews Cancer, Vol. 15, Issue 11 https://doi.org/10.1038/nrc4019	journal	October 2015
Genetic Dissection of TAM Receptor-Ligand Interaction in Retinal Pigment Epithelial Cell Phagocytosis Burstyn-Cohen, Tal; Lew, Erin D.; Través, Paqui G. Neuron, Vol. 76, Issue 6 https://doi.org/10.1016/j.neuron.2012.10.015	journal	December 2012
Paradoxical role of the proto-oncogene Axl and Mer receptor tyrosine kinases in colon cancer Bosurgi, L.; Bernink, J. H.; Delgado Cuevas, V. Proceedings of the National Academy of Sciences, Vol. 110, Issue 32 https://doi.org/10.1073/pnas.1302507110	journal	July 2013
Pancreatic cancer Li, Donghui; Xie, Keping; Wolff, Robert The Lancet, Vol. 363, Issue 9414 https://doi.org/10.1016/S0140-6736(04)15841-8	journal	March 2004
Development of an Orthotopic Model of Invasive Pancreatic Cancer in an Immunocompetent Murine Host Tseng, W. W.; Winer, D.; Kenkel, J. A. Clinical Cancer Research, Vol. 16, Issue 14 https://doi.org/10.1158/1078-0432.CCR-09-2384	journal	June 2010
AXL kinase as a novel target for cancer therapy Wu, Xiaoliang; Liu, Xuewen; Koul, Sanjay Oncotarget, Vol. 5, Issue 20 https://doi.org/10.18632/oncotarget.2542	journal	October 2014
An anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies Ye, X.; Li, Y.; Stawicki, S. Oncogene, Vol. 29, Issue 38 https://doi.org/10.1038/onc.2010.268	journal	July 2010
Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer Shah, Manish A.; Wainberg, Zev A.; Catenacci, Daniel V. T. PLoS ONE, Vol. 8, Issue 3 https://doi.org/10.1371/journal.pone.0054014	journal	March 2013
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
Inference of Macromolecular Assemblies from Crystalline State Krissinel, Evgeny; Henrick, Kim Journal of Molecular Biology, Vol. 372, Issue 3 https://doi.org/10.1016/j.jmb.2007.05.022	journal	September 2007
Notch blockade overcomes endothelial cell-mediated resistance of FLT3/ITD-positive AML progenitors to AC220 treatment Le, Quy; Hadland, Brandon; Meshinchi, Soheil Leukemia, Vol. 35, Issue 2 https://doi.org/10.1038/s41375-020-0893-y	journal	June 2020
axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase O'Bryan, J. P.; Frye, R. A.; Cogswell, P. C. Molecular and Cellular Biology, Vol. 11, Issue 10 https://doi.org/10.1128/mcb.11.10.5016-5031.1991	journal	October 1991
axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. R., Espinosa,; A., Frye, R.; P., O'Bryan, J. The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/nwsm-1d23	text	January 1991

Cited By (11)

GAS6-expressing and self-sustaining cancer cells in 3D spheroids activate the PDK-RSK-mTOR pathway for survival and drug resistance Baumann, Christine; Ullrich, Axel; Torka, Robert Molecular Oncology, Vol. 11, Issue 10 https://doi.org/10.1002/1878-0261.12109	journal	July 2017
Stromal Gas6 promotes the progression of premalignant mammary cells Gomes, Angelica M.; Carron, Emily C.; Mills, Kylie L. Oncogene, Vol. 38, Issue 14 https://doi.org/10.1038/s41388-018-0593-5	journal	December 2018
Tumor-associated macrophage-secreted 14-3-3ζ signals via AXL to promote pancreatic cancer chemoresistance D’Errico, Gabriele; Alonso-Nocelo, Marta; Vallespinos, Mireia Oncogene, Vol. 38, Issue 27 https://doi.org/10.1038/s41388-019-0803-9	journal	April 2019
AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells Kim, Donghwa; Bach, Duc-Hiep; Fan, Yan-Hua Cell Death & Disease, Vol. 10, Issue 5 https://doi.org/10.1038/s41419-019-1601-6	journal	May 2019
Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity Kimani, Stanley G.; Kumar, Sushil; Bansal, Nitu Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/srep43908	journal	March 2017
AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications Zhu, Chenjing; Wei, Yuquan; Wei, Xiawei Molecular Cancer, Vol. 18, Issue 1 https://doi.org/10.1186/s12943-019-1090-3	journal	November 2019
The bone marrow microenvironment in health and disease at a glance Kumar, Rahul; Godavarthy, P. Sonika; Krause, Daniela S. Journal of Cell Science, Vol. 131, Issue 4 https://doi.org/10.1242/jcs.201707	journal	February 2018
Soluble AXL as a marker of disease progression and survival in melanoma Flem-Karlsen, Karine; Nyakas, Marta; Farstad, Inger Nina PLOS ONE, Vol. 15, Issue 1 https://doi.org/10.1371/journal.pone.0227187	journal	January 2020
AXL Receptor Tyrosine Kinase as a Therapeutic Target in Hematological Malignancies: Focus on Multiple Myeloma Yan, Siyang; Vandewalle, Niels; De Beule, Nathan Cancers, Vol. 11, Issue 11 https://doi.org/10.3390/cancers11111727	journal	November 2019
Tumour-Secreted Protein S (ProS1) Activates a Tyro3-Erk Signalling Axis and Protects Cancer Cells from Apoptosis Al Kafri, Nour; Hafizi, Sassan Cancers, Vol. 11, Issue 12 https://doi.org/10.3390/cancers11121843	journal	November 2019
Dynamics of Axl Receptor Shedding in Hepatocellular Carcinoma and Its Implication for Theranostics Holstein, Elisa; Binder, Mathias; Mikulits, Wolfgang International Journal of Molecular Sciences, Vol. 19, Issue 12 https://doi.org/10.3390/ijms19124111	journal	December 2018

Similar Records

An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis

Journal Article · Sun Sep 21 00:00:00 EDT 2014 · Nature Chemical Biology · OSTI ID:1361055

Kariolis, Mihalis S.; Miao, Yu Rebecca; Jones, Douglas S.; +4 more

Imaging Axl expression in pancreatic and prostate cancer xenografts

Journal Article · Fri Jan 10 00:00:00 EST 2014 · Biochemical and Biophysical Research Communications · OSTI ID:1361055

Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala; +2 more

SAHA and cisplatin sensitize gastric cancer cells to doxorubicin by induction of DNA damage, apoptosis and perturbation of AMPK-mTOR signalling

Journal Article · Sat Sep 15 00:00:00 EDT 2018 · Experimental Cell Research · OSTI ID:1361055

Seah, Kwi Shan; Loh, Jian Yun; Nguyen, Thi Thuy Trang; +3 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES

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

Citation Formats

References (45)

Cited By (11)

Similar Records

Related Subjects