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

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.

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target

“…CXCL5 is up-regulated in M-RT4 cell line, which is a bladder cancer cell line and is resistant to mitomycin C. Reduced CXCL5 expression reduces the possibility of mitomycin C resistance [70]. Similarly, CXCL5 cytokine showed significant upregulation in sunitinib-resistant cells [71]. CXCL5 can be used as a predictor of lysosomotropic drug resistance (sunitinib and lapatinib) which contributes to autophagy and inflammatory responses in breast and kidney cancer.…”

“…CXCL5 can be used as a predictor of lysosomotropic drug resistance (sunitinib and lapatinib) which contributes to autophagy and inflammatory responses in breast and kidney cancer. Researchers believed that CXCL5 cannot predict the efficacy of bevacizumab guided by VEGF [71]. Second, CXCL5 was observed to be associated with end-stage cancer and sunitinib recurrence rates [71].…”

“…Researchers believed that CXCL5 cannot predict the efficacy of bevacizumab guided by VEGF [71]. Second, CXCL5 was observed to be associated with end-stage cancer and sunitinib recurrence rates [71]. Therefore, an examination to evaluate CXCL5 in the tissues should be conducted to guide further treatment.…”

“…Inhibit the establishment of early metastatic microenvironment [40] Restrain tumor progression [7,47,69] Reduce resistance to targeted drugs [47,70,71] Inhibit tumor angiogenesis [53,68] Enhance drug utility [68,72,73] assisting paclitaxel is considered to be safe and has no mutual pharmacokinetic effects (NCT02001974) [75]. Relevant clinical applications are should be conducted to improve the survival time of patients (Table 3).…”

Neuropilin 1 and Neuropilin 2 Gene Invalidation or Pharmacological Inhibition Reveals Their Relevance for the Treatment of Metastatic Renal Cell Carcinoma

“…Hence, we analyzed the expression of VEGFA and VEGFC following NRPa-308 treatment. We also determined the expression of the ELR + CXCL cytokines CXCL5 and CXCL8 since they are involved in resistance to bevacizumab and sunitinib in ccRCC as we previously described [16,25]. Sunitinib, at these low concentrations (below the IC50 [24]), had no in uence on VEGFA and VEGFC expression but increased CXCL5 and CXCL8 expression as previously shown (Fig.…”