Axl molecular targeting counteracts aggressiveness but not platinum-resistance of ovarian carcinoma cells

Corno, Cristina; Gatti, Laura; Arrighetti, Noemi; Carenini, Nives; Zaffaroni, Nadia; Lanzi, Cinzia; Perego, Paola

doi:10.1016/j.bcp.2017.04.002

Cited by 14 publications

(23 citation statements)

References 32 publications

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“…An increased aggressiveness of IGROV-1/Pt1 cells in terms of migratory and invasive abilities has been linked to Axl overexpression [27]. Of note, here we observed that all conjugates 1 – 3 were capable of inhibiting cell migration in both IGROV-1 and IGROV-1/Pt1, with a striking effect of compound 3 on the migratory ability of resistant cells that was almost completely abolished (Figure 4).…”

Section: Discussionsupporting

confidence: 55%

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

Sartori

Corno

Cesare

et al. 2019

Cancers

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Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are also deregulated in cancer and their expression has been associated with drug resistance. Here, the antitumor effects of three conjugates possessing a selective binder of the extracellular portion of integrin αVβ3 covalently linked to the tyrosine kinase inhibitor sunitinib were investigated in cisplatin-sensitive and -resistant ovarian carcinoma cells expressing both tyrosine kinase VEGFR2 and αVβ3 at different levels. We found that one of the three compounds was active in inhibiting the growth of both drug-sensitive and -resistant cells in the micromolar range with a slightly increased potency in resistant cells as compared to sunitinib. The same compound markedly impaired cell migratory and invasive abilities and reduced paxillin phosphorylation. Antitumor activity studies in IGROV-1/Pt1 cells xenografted in nude mice revealed a striking activity of this conjugate versus sunitinib. Taken together, our results support the interest of integrin-targeted sunitinib conjugates for the treatment of drug-resistant tumors.

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Section: Discussionsupporting

confidence: 55%

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

Sartori

Corno

Cesare

et al. 2019

Cancers

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“…Macleod found that AXL mRNA levels were 3-fold higher in platinum-resistant ovarian cancer cell lines than in platinumsensitive cell lines (15). Corno and colleagues recently published that AXL expression correlated with aggressiveness of ovarian cancers, but they found that AXL inhibition did not increase chemosensitivity of the IGROV1-Pt1 cell line (17). In contrast, Kariolis and colleagues showed that AXL inhibition increased ovarian cancer response to the second-line/third-line chemotherapy drug doxorubicin (14).…”

Section: Discussionmentioning

confidence: 99%

“…Further, AXL was one of several genes found to be amplified in ovarian cancer cells conditioned in platinum (15,16). Corno and colleagues demonstrate no significant impact of AXL inhibition on platinum sensitivity in the IGROV-Pt1 cell line (17), while Kanlikilicer and colleagues report a novel AXL inhibitor improves response to paclitaxel, but only in an intraperitoneal mouse model and without mechanistic investigation (8). However, no work has yet addressed whether or not AXL expression contributes to ovarian cancer resistance to the standard-of-care treatments paclitaxel and carboplatin and a mechanism by which this occurs.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer

Quinn

Greenwade

Palisoul

et al. 2019

Molecular Cancer Therapeutics

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Ovarian cancer, one of the deadliest malignancies in female cancer patients, is characterized by recurrence and poor response to cytotoxic chemotherapies. Fewer than 30% of patients with resistant disease will respond to additional chemotherapy treatments. This study aims to determine whether and how inhibition of the receptor tyrosine kinase AXL can restore sensitivity to first-line platinum and taxane therapy in ovarian cancer. AXL staining was quantified in a patient tissue microarray and correlated with chemoresponse of patients. We used small hairpin RNAs to knock down AXL expression and the small-molecule inhibitor BGB324 to inhibit AXL and assessed sensitivity of cell lines and primary patientderived cells to chemotherapy. We quantified platinum accumulation by inductivity-coupled plasma phase mass spectrometry. Finally, we treated chemoresistant patient-derived xenografts with chemotherapy, BGB324, or chemotherapy plus BGB324 and monitored tumor burden. AXL expression was higher in chemoresistant patient tumors and cell lines than in chemosensitive tumors and cell lines. AXL staining significantly predicted chemoresponse. Knockdown and inhibition of AXL dose-dependently improved response to paclitaxel and carboplatin in both cell lines and primary cells. AXL inhibition increased platinum accumulation by 2-fold (*, P < 0.05). In vivo studies indicated that AXL inhibition enhanced the ability of chemotherapy to prevent tumor growth (****, P < 0.0001). AXL contributes to platinum and taxane resistance in ovarian cancer, and inhibition of AXL improves chemoresponse and accumulation of chemotherapy drugs. This study supports continued investigation into AXL as a clinical target.

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“…Western blot analysis was carried out as described (Corno et al, 2017). Briefly, samples were fractionated by SDS-PAGE and blotted on nitrocellulose membranes.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Data analysis was performed with RQ manager software (Applied Biosystems). Relative levels of cDNA were determined as previously described (Corno et al, 2017), through the relative quantification (RQ) method. Untransfected or control cells were chosen as calibrator.…”

Section: Quantitative Real Time Pcrmentioning

confidence: 99%

Synergistic Interaction of Histone Deacetylase 6- and MEK-Inhibitors in Castration-Resistant Prostate Cancer Cells

Corno

Arrighetti

Ciusani

et al. 2020

Front. Cell Dev. Biol.

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In spite of new knowledge on prostate cancer molecular landscape, this has been only partially translated to the therapeutic setting. The activation of Ras/Mitogen-activated protein kinase (MAPK) signaling plays an important role in progression of prostate cancer in which deregulation of histone deacetylases (HDAC) is frequent. Based on the notion that HDAC inhibitors may reactivate the expression of genes favoring cell response to drugs, the aim of this study was to investigate the interaction between the HDAC6specific inhibitor ricolinostat (ACY1215) and the MEK-inhibitor selumetinib (AZD6244) to identify effective combinations in prostate cancer models. Using cell lines exhibiting differential activation of survival pathways (PC3, DU145, 22Rv1) and following different treatment schedules, a synergistic interaction was observed in all cell models, the drug combination being particularly effective in 22Rv1 cells. Marginal levels of apoptosis were observed in PC3 cells after combined treatment, whereas higher levels were achieved in DU145 and 22Rv1 cells. RNAi-mediated knockdown of HDAC6 in selumetinibtreated 22Rv1 cells resulted in increased apoptosis. Combined treatment suppressed the constitutively deregulated survival pathways in all cell lines. A decrease of androgen receptor (AR)-dependent gene (KLK2, DUSP1) mRNA levels was observed in 22Rv1 treated cells, associated with increased AR cytoplasmatic expression, suggesting AR signaling down-regulation, not involving Hsp90 acetylation. When a taxane was used in combination with AZD6244 and ACY1215 by a simultaneous schedule, a synergistic cytotoxic effect together with increased apoptosis was evidenced in all cell models. These results support a rational use of targeted agents to improve prostate cancer cell apoptotic response.

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Axl molecular targeting counteracts aggressiveness but not platinum-resistance of ovarian carcinoma cells

Cited by 14 publications

References 32 publications

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

Efficacy of a Selective Binder of αVβ3 Integrin Linked to the Tyrosine Kinase Inhibitor Sunitinib in Ovarian Carcinoma Preclinical Models

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer

Synergistic Interaction of Histone Deacetylase 6- and MEK-Inhibitors in Castration-Resistant Prostate Cancer Cells

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