Platinum-based therapy, combined or not with immune checkpoint inhibitors, represents a front-line choice for patients with non-small-cell lung cancer (NSCLC). Despite the improved outcomes in the ...last years for this malignancy, only a sub-group of patients have long-term benefit. Excision repair cross-complementation group 1 (ERCC1) has been considered a potential biomarker to predict the outcome of platinum-based chemotherapy in NSCLC. However, the ERCC1 gene is transcribed in four splice variants where the isoform 202 was described as the only one active and able to complex Xeroderma pigmentosum group F-complementing protein (XPF). Here, we prospectively investigated if the active form of ERCC1, as assessed by the ERCC1/XPF complex (ERCC1/XPF), could predict the sensitivity to platinum compounds.
Prospectively enrolled, patients with advanced NSCLC treated with a first-line regimen containing platinum were centrally evaluated for ERCC1/XPF by a proximity ligation assay. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were analyzed.
The absence of the ERCC1/XPF in the tumor suggested a trend of worst outcomes in terms of both OS hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.67-2.94, P = 0.373 and PFS (HR 1.61, 95% CI 0.88-3.03, P = 0.123). ORR was marginally influenced in ERCC1/XPF-negative and -positive groups odds ratio (stable disease + progressive disease versus complete response + partial response) 0.87, 95% CI 0.25-3.07, P = 0.832.
The lack of ERCC1/XPF complex in NSCLC tumor cells might delineate a group of patients with poor outcomes when treated with platinum compounds. ERCC1/XPF absence might well identify patients for whom a different therapeutic approach could be necessary.
•This is the first study investigating the ERCC1/XPF complex as a platinum-based therapy response biomarker in NSCLC.•The lack of ERCC1/XPF complex might delineate a group of patients with poor outcomes when treated with platinum compounds.•ERCC1/XPF absence might identify tumors for whom a different therapeutic approach than platinum compounds could be necessary.
IntroductionOne of the main obstacle to the successful development of therapeutic strategies remains the identification of biomarker underlying drug resistance. Recently, investigators have become ...more aware the role of the tumour microenvironment (TME) in cancer and the potential therapeutic opportunities that derive from suppressing potential resistance mechanisms arising microenvironmental interactions. The aim of this study was to set-up multicellular culture models to uncover the molecular mechanisms by which stromal/endothelial cells modulate response to signalling inhibitors and to identify potential therapeutic targets in PTEN-loss contexts.Material and methodsIsogenic CRC cell lines (X-MAN HCT116 and HCT116 PTEN-/-) were treated with MAPKi and PI3K/mTORi alone or in combination, in the presence or absence of stromal fibroblasts or fibroblast/endothelial cell conditioned medium (CM). Cytofluorimetric analysis and Crystal Violet assay were used to analyse functional response to targeted agents; pathways activation and cytokine/chemokine profile were analysed using Western blot and ELISA assay respectively.Results and discussionsIn co-culture CRC models, the response to MAPK and PI3K inhibitors is the result of interaction between tumour cells and their surrounding stroma. Response to PI3K/mTORi is mainly influenced by microenvironmental interactions: direct cell-to-cell tumour/stroma contact renders stromal cells resistant to PI3K/mTORi, while the presence of stromal cell-derived soluble factors sensitises PTEN-competent CRC cells to PI3K/mTORi-mediated growth inhibition. This effect was confirmed using CM from different types of stromal cells (fibroblast/endothelial) that similarly affected the response of CRC cell lines to signalling inhibitors; this is probably due to similar profile of cytokine/chemokine production in stromal cell and is subjected to a ‘saturation’ effect. The presence of stromal CM upregulates MAPK activation regardless of PTEN status, whereas mTOR pathway upregulation is observed mainly in PTEN-competent CRC cells.ConclusionThe presence of stromal cells (fibroblasts/endothelium) profoundly influences CRC response to PI3K/mTOR-targeting agents. Understanding the mechanisms underlying microenvironmental interactions (tumour, stroma, soluble factors) may be of fundamental importance to overcome therapeutic resistance and develop more effective therapies for patients affected by cancer.
XIAP is a member of the inhibitors-of-apoptosis family of proteins, which inhibit caspases and block cell death, with prognostic importance in AML. Here we demonstrate that cytokines regulate the ...expression of XIAP in leukemic cell lines and primary AML blasts. Inhibition of phosphatidylinositol-3 kinase (PI3K) with LY294002 and of the mitogen-activated protein kinase (MAPK) cascade by PD98059 resulted in decreased XIAP levels (34+/-8.7 and 23+/-5.7%, respectively). We then generated OCI-AML3 cells with constitutively phosphorylated Akt (p473-Akt) by retroviral gene transfer. Neither these nor Akt inhibitor-treated OCI-AML3 cells showed changes in XIAP levels, suggesting that XIAP expression is regulated by PI3K downstream effectors other than Akt. The induction of XIAP expression by cytokines through PI3K/MAPK pathways is consistent with its role in cell survival. Exposure of leukemic cells to chemotherapeutic agents decreased XIAP protein levels by caspase-dependent XIAP cleavage. Targeting XIAP by XIAP antisense oligonucleotide resulted in downregulation of XIAP, activation of caspases and cell death, and sensitized HL-60 cells to Ara-C. Our results suggest that XIAP is regulated by cytokines through PI3K, and to a lesser degree through MAPK pathways. Selective downregulation of XIAP expression might be of therapeutic benefit to leukemic patients.
PDF
