Novel Axl-driven signaling pathway and molecular signature characterize high-grade ovarian cancer patients with poor clinical outcome

Rea, Katia; Pinciroli, Patrizia; Sensi, Marialuisa; Alciato, Federica; Bisarò, Brigitte; Lozneanu, Ludmila; Raspagliesi, Francesco; Centritto, Floriana; Cabodi, Sara; Defilippi, Paola; Avanzi, Gian Carlo; Canevari, Silvana; Tomassetti, Antonella

doi:10.18632/oncotarget.5087

Cited by 32 publications

(28 citation statements)

References 35 publications

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“…AXL has recently emerged as a promising therapeutic target in ovarian cancer [3,9] where it is overexpressed and confers poor prognosis [3,39,40]. The resultant poor overall survival in the advanced disease state creates great unmet need to find therapeutically relevant targets to improve patient outcome.…”

Section: Discussionmentioning

confidence: 99%

“…The resultant poor overall survival in the advanced disease state creates great unmet need to find therapeutically relevant targets to improve patient outcome. AXL has recently emerged as a promising therapeutic target in ovarian cancer [3,9] where it is overexpressed and confers poor prognosis [3,39,40]. However, the biology of AXL regulation remains to be elucidated, and understanding of these regulatory mechanisms will serve to identify novel targets and design appropriate drug candidates targeting relevant biology.…”

Section: Discussionmentioning

confidence: 99%

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The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer

et al. 2018

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In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 and We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL-dependent oncogenic signalling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer

et al. 2018

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“…Immunohistochemical analysis of primary tumors revealed that AXL expression correlates with metastasis and/or poor survival in patients with lung adenocarcinoma, glioblastoma multiforme, pancreatic, renal cell carcinoma, esophageal adenocarcinoma, oral squamous carcinoma, pleural mesothelioma, ovarian adenocarcinoma, colon cancer, head and neck squamous cell carcinoma, urothelial carcinoma, esophageal cell carcinoma, and hepatocellular carcinoma (Table 1, [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28]). Moreover, AXL expression correlates with drug resistance in patients with melanoma, myeloid leukemia, lung cancer, and renal cell carcinoma [29,30,31,32,33,34].…”

Section: Gas6 and Axl Expression In Cancermentioning

confidence: 99%

The Receptor Tyrosine Kinase AXL in Cancer Progression

Rankin

Giaccia

2016

Cancers

133

102

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The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy.

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“…This phenotype is mechanistically explained, at least in part, by the AXL-mediated phosphorylation of engulfment and cell motility scaffold protein that, in turn, promotes Rac-mediated cytoskeleton changes, resulting in increased cancer cell migration (28). Accordingly, this is reversed by both AXL and Rac inhibition (29). …”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

Scaltriti

Elkabets

Baselga

2016

Clinical Cancer Research

100

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AXL is a tyrosine kinase membrane receptor that signals via PI3K, MAPK, and protein kinase C (PKC), among other pathways. AXL has oncogenic potential and interacts with other membrane receptors, depending on their relative abundance and availability. The increased expression of AXL in cancer is often the result of pharmacologic selective pressure to a number of chemotherapies and targeted therapies and acts as a mechanism of acquired drug resistance. This resistance phenotype, frequently accompanied by epithelial-to-mesenchymal transition, can be reversed by AXL inhibition. In tumors with high levels of EGFR, including lung, head and neck, and triple-negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvents the antitumor effects of anti-EGFR therapies. Likewise, AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-γ-PKC cascade that, in turn, sustains mTORC1 activity. The causative role of AXL in inducing drug resistance is underscored by the fact that the suppression of AXL restores sensitivity to these agents. Hence, these observations indicate that AXL is selectively expressed in tumor cells refractory to therapy and that cotargeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic.

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Novel Axl-driven signaling pathway and molecular signature characterize high-grade ovarian cancer patients with poor clinical outcome

Cited by 32 publications

References 35 publications

The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer

The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer

The Receptor Tyrosine Kinase AXL in Cancer Progression

Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

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