A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

Mahadevan, Daruka; Cooke, Laurence; Riley, Christopher; Swart, Rachel; Simons, Brian W.; Croce, Kimiko Della; Wisner, Lee; Iorio, Marilena V.; Shakalya, Kishore; Hs, Garewal; Nagle, Raymond B.; Bearss, David J.

doi:10.1038/sj.onc.1210173

Cited by 255 publications

(202 citation statements)

References 35 publications

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“…AXL is characterized by a unique extracellular composition consisting of immunoglobulin-like and fibronectin-type III-like domains, which are also found in adhesion molecules of the cadherin and immunoglobulin superfamily, therefore suggesting that AXL might regulate cell adhesion (Burchert et al, 1998). Other evidence is consistent with roles of AXL in tumor cell invasion, metastasis and survival (Jacob et al, 1999;Holland et al, 2005;Mahadevan et al, 2007).…”

Section: Introductionmentioning

confidence: 72%

AXL regulates mesothelioma proliferation and invasiveness

et al. 2010

Oncogene

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Mesothelioma is an asbestos-associated and notoriously chemotherapy-resistant neoplasm. Activation of the receptor tyrosine kinases (RTKs), epidermal growth factor receptor and MET, has been described in subsets of mesothelioma, suggesting that TKs might represent therapeutic targets in this highly lethal disease. We employed proteomic screening by phosphotyrosine immunoaffinity purification and tandem mass spectrometry to characterize RTK activation in mesothelioma cell lines. These assays demonstrated expression and activation of the AXL protein, which is an RTK with known oncogenic properties in non-mesothelial cancer types. AXL was expressed and activated strongly in 8 of 9 mesothelioma cell lines and 6 of 12 mesothelioma biopsies, including each of 12 mesotheliomas with spindle-cell histology. Somatic AXL mutations were not found, but all mesotheliomas expressed an alternatively spliced AXL transcript with in-frame deletion of exon 10, and six of seven mesothelioma cell lines expressed the AXL ligand, growth arrest-specific 6 (GAS6). GAS6 expression appeared to be functionally relevant, as indicated by modulation of AXL tyrosine phosphorylation by knockdown of endogeneous GAS6, and by administration of exogenous GAS6. AXL silencing by lentivirus-mediated short hairpin RNA suppressed mesothelioma migration and cellular proliferation due to G1 arrest. The AXL inhibitor DP-3975 inhibited cell migration and proliferation in mesotheliomas with strong AXL activation. DP-3975 response in these tumors was characterized by inhibition of PI3-K/AKT/mTOR and RAF/MAPK signaling. AXL inhibition suppressed mesothelioma anchorage-independent growth, with reduction in colony numbers and size. These studies suggest that AXL inhibitors warrant clinical evaluation in mesothelioma.

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Section: Introductionmentioning

confidence: 72%

AXL regulates mesothelioma proliferation and invasiveness

et al. 2010

Oncogene

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“…RTKs are a well-established cancer therapeutic class, and small molecule inhibitors of Axl tyrosine kinase activity have been reported (27,28). Interestingly, Her2 is reported to trigger Axl activation, suggesting crosstalk with this clinically important pathway (29).…”

Section: Discussionmentioning

confidence: 99%

Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival

Gjerdrum

Tiron²,

Høiby³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

520

557

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Metastasis underlies the majority of cancer-related deaths. Thus, furthering our understanding of the molecular mechanisms that enable tumor cell dissemination is a vital health issue. Epithelialto-mesenchymal transitions (EMTs) endow carcinoma cells with enhanced migratory and survival attributes that facilitate malignant progression. Characterization of EMT effectors is likely to yield new insights into metastasis and novel avenues for treatment. We show that the presence of the receptor tyrosine kinase Axl in primary breast cancers independently predicts strongly reduced overall patient survival, and that matched patient metastatic lesions show enhanced Axl expression. We demonstrate that Axl is strongly induced by EMT in immortalized mammary epithelial cells that establishes an autocrine signaling loop with its ligand, Gas6. Epiallelic RNA interference analysis in metastatic breast cancer cells delineated a distinct threshold of Axl expression for mesenchymal-like in vitro cell invasiveness and formation of tumors in foreign and tissue-engineered microenvironments in vivo. Importantly, in two different optical imagingbased experimental breast cancer models, Axl knockdown completely prevented the spread of highly metastatic breast carcinoma cells from the mammary gland to lymph nodes and several major organs and increased overall survival. These findings suggest that Axl represents a downstream effector of the tumor cell EMT that is required for breast cancer metastasis. Thus, the detection and targeted treatment of Axl-expressing tumors represents an important new therapeutic strategy for breast cancer.carcinoma | receptor tyrosine kinase | breast cancer

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“…Recently, by profiling of phosphotyrosine signaling, activated Axl protein was detected in about 5% primary tumors of non-small-cell lung cancer (NSCLC) (Rikova et al, 2007). Expression of Axl is induced by targeted and chemotherapy drugs and drug-induced Axl expression confers resistance to chemotherapy in acute myeloid leukemia (Hong et al, 2008) as well as resistance to imatinib and lapatinib/herceptin in gastrointestinal stromal tumors (Mahadevan et al, 2007) and breast cancer , respectively.…”

Section: Introductionmentioning

confidence: 99%