ABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy (CT) are the current standard of therapy in several cancer types. Patients (pts) with lung cancer display higher response rates to CT when given after ICIs. Although ICIs have failed to demonstrate antitumour activity in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), little is known about CT effect after ICIs. We aimed to assess whether sequential ICIs followed by CT may be an alternative therapeutic approach in a population of pts with mCRC. MATERIAL AND METHODS: We retrospectively assessed CT after ICI (CAICI) failure in pts with mCRC. The ICI regimen consisted of anti-PD(L)1 alone or in combination. The primary end-point was objective response rate. Progression-free survival (PFS) and overall survival (OS) were secondary end-points. RESULTS: Between 2014 and 2018, 29 pts with mCRC received CAICI (MSS tumours, 27 pts [86%]). The median number of previous lines was 4 (range, 2-7). Regimens included TAS-102 (n = 14), FOLFIRI (irinotecan, leucovorin, and fluorouracil; n = 6) or FOLFOX (oxaliplatin, leucovorin, and fluorouracil; n = 4), regorafenib (n = 3) and carboplatin (1 pt with BRCA mutation). Partial response and stable disease were observed in 4 (19%) and 9 (43%) pts, respectively (disease control rate, 62%). The median PFS and OS were 3.8 months (95% confidence interval [CI] = 1.5-5.4) and 8.0 months (95% CI = 4.2-14.0), respectively. CONCLUSION: ICIs administered before CT might enhance cytotoxic effects even in pts with immunorefractory MSS mCRC. The results of this small cohort need to be validated in independent prospective cohorts. The role of ICIs as modifiers of both tumour cells and microenvironment in mCRC deserves further research.
Subject(s)
Colorectal Neoplasms/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Humans , Immune Checkpoint Inhibitors/pharmacology , Male , Middle Aged , Retrospective StudiesABSTRACT
Renal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies.
Subject(s)
Angiogenesis Inhibitors/adverse effects , Carrier Proteins/metabolism , Kidney Diseases/chemically induced , Kidney Glomerulus/drug effects , Niacinamide/analogs & derivatives , Phenylurea Compounds/adverse effects , Protein Kinase Inhibitors/adverse effects , Transcription Factor RelA/metabolism , Vascular Endothelial Growth Factors/antagonists & inhibitors , Adaptor Proteins, Signal Transducing , Adult , Aged , Animals , Base Sequence , Binding Sites , Biomarkers/metabolism , Carrier Proteins/genetics , Case-Control Studies , Cell Line , Female , Gene Expression Regulation , Glomerulosclerosis, Focal Segmental/chemically induced , Glomerulosclerosis, Focal Segmental/diagnosis , Glomerulosclerosis, Focal Segmental/enzymology , Humans , Hypertension/chemically induced , Hypertension/diagnosis , Hypertension/enzymology , Kidney Diseases/diagnosis , Kidney Diseases/enzymology , Kidney Glomerulus/enzymology , Kidney Glomerulus/pathology , Male , Mice , Mice, Knockout , Middle Aged , Molecular Sequence Data , Nephrosis, Lipoid/chemically induced , Nephrosis, Lipoid/diagnosis , Nephrosis, Lipoid/enzymology , Niacinamide/adverse effects , Predictive Value of Tests , Promoter Regions, Genetic , Proteinuria/chemically induced , Proteinuria/diagnosis , Proteinuria/enzymology , Renal Insufficiency/chemically induced , Renal Insufficiency/diagnosis , Renal Insufficiency/enzymology , Sorafenib , Thrombotic Microangiopathies/chemically induced , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/enzymology , Transcription Factor RelA/deficiency , Transcription Factor RelA/genetics , Transcription, Genetic , Transfection , Vascular Endothelial Growth Factors/metabolism , Young AdultSubject(s)
Alkalosis/metabolism , Hypertension/complications , Hypokalemia/metabolism , Lung Neoplasms/pathology , Small Cell Lung Carcinoma/pathology , Aged , Alkalosis/diagnosis , Cushing Syndrome/diagnosis , Cushing Syndrome/epidemiology , France/epidemiology , Humans , Hypertension/diagnosis , Hypokalemia/diagnosis , Ketoconazole/therapeutic use , Lung Neoplasms/diagnosis , Male , Neoplasm Staging , Paraneoplastic Endocrine Syndromes/diagnosis , Paraneoplastic Endocrine Syndromes/epidemiology , Small Cell Lung Carcinoma/diagnosis , Treatment OutcomeABSTRACT
Overexpression of several aquaporins has been reported in different types of human cancer but the role of AQPs in human carcinogenesis has not yet been clearly defined. Here, we demonstrate that ectopic expression of human AQP5 (hAQP5), a water channel expressed in lung, salivary glands, and kidney, induces many phenotypic changes characteristic of transformation both in vitro and in vivo. Furthermore, the cell proliferative ability of AQP5 appears to be dependent upon the phosphorylation of a cAMP-protein kinase (PKA) consensus site located in a cytoplasmic loop of AQP5. In addition, phosphorylation of the PKA consensus site was found to be phosphorylated preferentially in tumors. These findings altogether indicate that hAQP5 plays an important role in human carcinogenesis and, furthermore, provide an attractive therapeutic target.
