Theranostics 2019; 9(4):1181-1199. doi:10.7150/thno.29093

Research Paper

Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5

Sandy Giuliano1, Maeva Dufies1*, Papa Diogop Ndiaye2*, Julien Viotti3, Delphine Borchiellini4, Julien Parola2, Valérie Vial1, Yann Cormerais1, Mickaël Ohanna5, Véronique Imbert5, Emmanuel Chamorey3, Nathalie Rioux-Leclercq6, Ariel Savina7, Jean-Marc Ferrero4, Baharia Mograbi2, Gilles Pagès2✉

1. Centre Scientifique de Monaco, Biomedical Department, 8 Quai Antoine Ier, MC-98000 Monaco, Principality of Monaco.
2. University Cote d'Azur (UCA), Institute for research on cancer and aging of Nice, CNRS UMR 7284; INSERM U1081, Centre Antoine Lacassagne, France.
3. Centre Antoine Lacassagne, Statistic department, Nice, France
4. Centre Antoine Lacassagne, Clinical research department, Nice, France
5. Centre Méditerranéen de Médecine Moléculaire, Nice, France
6. Department of Pathology, University Hospital, Rennes, France
7. Roche Institute
*These authors contributed equally

Abstract

Lysosomotropic agents such as sunitinib, lapatinib, and chloroquine belong to a drug family that is being used more frequently to treat advanced cancers. Sunitinib is standard care for metastatic renal cell carcinomas (mRCC) and lapatinib is used for trastuzumab/pertuzumab-refractory cancers. However, patients ineluctably relapse with a delay varying from a few months to a few years. To improve reactivity prior to relapse it is essential to identify the mechanisms leading to such variability. We showed previously that sunitinib became sequestered in lysosomes because of its basic pKa.

Methods: Modifications to gene expression in response to sunitinib and in sunitinib resistant cells were analyzed by transcriptomic and proteomic analysis. ROS production was evaluated by FACS. Nuclear Factor kappa B (NFkB)-dependent transcriptional regulation of inflammatory gene expression was evaluated with a reporter gene. Correlation of CXCL5 with survival was analyzed with an online available data base (TCGA) and using a cohort of patients enrolled in the SUVEGIL clinical trial (NCT00943839).

Results: We now show that sunitinib sequestration in lysosomes induced an incomplete autophagic process leading to activation of the NFkB inflammatory pathway. We defined a subset of inflammatory cytokines that were up-regulated by the drug either after an acute or chronic stimulus. One of the most up-regulated genes in sunitinib-resistant cells was the CXCL5 cytokine. CXCL5 was also induced in RCC by chloroquine and in a model of HER2 positive breast cancer cell lines after acute or chronic treatment with lapatinib. CXCL5 correlated to shorter survival in RCC and to the most aggressive forms of breast cancers. The levels of CXCL5 present in the plasma of patients treated with sunitinib were predictive of the efficacy of sunitinib but not of the VEGF-directed antibody bevacizumab.

Conclusion: This translational study identified CXCL5 as a biomarker of efficacy of lysosomotropic drugs, a potential asset for personalized medicine.

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How to cite this article:
Giuliano S, Dufies M, Ndiaye PD, Viotti J, Borchiellini D, Parola J, Vial V, Cormerais Y, Ohanna M, Imbert V, Chamorey E, Rioux-Leclercq N, Savina A, Ferrero JM, Mograbi B, Pagès G. Resistance to lysosomotropic drugs used to treat kidney and breast cancers involves autophagy and inflammation and converges in inducing CXCL5. Theranostics 2019; 9(4):1181-1199. doi:10.7150/thno.29093. Available from http://www.thno.org/v09p1181.htm