Gas6-Axl signaling in presence of Sunitinib is enhanced, diversified and sustained in renal tumor cells, resulting in tumor-progressive advantages.
Clear Cell Renal Cell Carcinoma (CCRCC) is a lethal cancer with bad prognosis due to development of chemoresistance and recurrence of more aggressive tumors. Investigation of Gas6-mediated Axl signaling in CCRCC and endothelial cells reveals a Sunitinib resistant Gas6-Axl signaling that is sustained and enhanced and specifically triggers downstream AKT and PRAS40 activation in an intensified manner. Gas6-induced Axl signaling in presence of Sunitinib is also diversified displaying onset of Axl-dependent EGFR and METR activation and activation of classical MAPK pathways. Gas6+Sunitinib-adapted CCRCC cells present increased viability and decreased apoptosis and enhanced production of the multi-tumorigenic Osteopontin (OPN) and of one of its activator matrix metalloproteinase-7. Axl activity is necessary for CCRCC cell sphere formation and the ability of the cells to attach after non-adhesive growth. In addition, Gas6+Sunitinib-adapted CCRCC cells displayed enhanced migration and sphere formation, both mechanisms being Axl and OPN dependent. Altogether, this suggests that Sunitinib while targeting endothelial cells and tumor angiogenesis, simultaneously provides protumorigenic effects due to a constitutively, intensified and divergent Gas6-Axl system.



Gas6-mediated Axl signaling, which is enhanced and diversified in the presence of Sunitinib possibly contributes to acquired chemoresistance, recurrence of aggressive disease and metastasis of CCRCC tumors. Therefore, combinatorial Axl-targeted therapy might be beneficial for CCRCC patients intended for Sunitinib treatment.
Lund University, Department of Translational Medicine, Section of Clinical Chemistry, University Hospital Malmö, Malmö, Sweden. Electronic address: Anna.Gustafsson@med.lu.se.
Anna
A
Gustafsson
Lund University, Department of Translational Medicine, Section of Clinical Chemistry, University Hospital Malmö, Malmö, Sweden.
Helena K M
HKM
Fritz
Lund University, Department of Translational Medicine, Section of Clinical Chemistry, University Hospital Malmö, Malmö, Sweden.
Björn
B
Dahlbäck
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000077210:Sunitinib; D014407:Tumor Cells, Cultured; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D000970:Antineoplastic Agents; D007211:Indoles; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human
Drug resistance; Novel mechanism; Receptor tyrosine kinases; Renal cancer; Tumor progression; Tumor promotion