Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies

Stommel, Jayne M.; Kimmelman, Alec C.; Ying, Haoqiang; Nabioullin, Roustem; Ponugoti, Aditya H.; Wiedemeyer, Ruprecht; Stegh, Alexander H.; Bradner, James E.; Ligon, Keith L.; Brennan, Cameron; Chin, Lynda; DePinho, Ronald A.

doi:10.1126/science.1142946

Cited by 824 publications

(762 citation statements)

References 16 publications

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“…Interactions between AXL and PI3-K were blocked in a dose-dependent manner by the AXL inhibitor, DP-3975 (Figure 4a), suggesting that AXL regulation of PI3-K/AKT/mTOR signaling requires AXL:PI3-K interaction. AKT is a crucial intermediate in RTK/PI3-K signaling, with contributions to cell proliferation, survival and migration/ invasiveness, depending on cell context (Sordella et al, 2004;Stommel et al, 2007;Harir et al, 2008;Faber et al, 2009). Soft agarose assays confirmed that the PI3-K/AKT/mTOR signaling pathway contributes to AXL-mediated mesothelioma tumorigenic properties (Supplementary Figure 2A and 2C).…”

Section: Discussionmentioning

confidence: 81%

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: Discussionmentioning

confidence: 81%

AXL regulates mesothelioma proliferation and invasiveness

et al. 2010

Oncogene

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“…2E). Saracatinib markedly reduced phosphorylation of c-Src at Thy419 (lanes [8][9][10][11][12][13][14], indicating that it inhibited c-Src kinase activity. It also decreased phosphorylation of EGFR and Shc in the absence of gefitinib (lane 8), resulting in inhibition of Ras-c-Raf-MEK1/2-ERK1/2 cell signaling.…”

Section: Significancementioning

confidence: 99%

“…After immunoprecipitation with EGFR antibodies (Fig. 2C), mutated EGFR associated directly with c-Src in the absence of gefitinib (lane 8), and EGFR inhibition did not alter this association (lanes [9][10][11][12][13][14]. Because EGFR and c-Src were consistently localized in the plasma membrane, regardless of EGFR phosphorylation status (Fig.…”

Section: Significancementioning

confidence: 99%

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EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

Phuchareon

McCormick

Eisele

et al. 2015

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

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Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.nonsmall cell lung cancer | EGFR inhibition | tyrosine kinase inhibitors | ERK1/2 paradoxical activation | innate drug resistance

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“…4,18,19 Moreover, Met confers resistance to ErbB antagonists, as cancer cells use Met to maintain the RTK-driven oncogenic pathways active. [20][21][22] Here, we show that genetic and pharmacological knockdown of c-Abl impairs Met-triggered solid tumor formation in vivo. By investigating the molecular mechanism involved, we identified a novel signaling path by which c-Abl interconnects RTKs and p53 core pathways.…”

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confidence: 99%

Abl interconnects oncogenic Met and p53 core pathways in cancer cells

et al. 2011

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The simplicity of BCR-ABL 'oncogene addiction' characterizing leukemia contrasts with the complexity of solid tumors where multiple 'core pathways', including receptor tyrosine kinases (RTKs) and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared with the impact of Imatinib in BCR-ABL-dependent leukemia. Here, we identified c-Abl as a signaling node interconnecting Met-RTK and p53 core pathways, and showed that its inhibition impairs Met-dependent tumorigenesis. Met ensures cell survival through a new path in which c-Abl and p38-MAPK are employed to elicit p53 phosphorylation on Ser(392) and Mdm2 upregulation. We found a clinical correlation between activated Met, phospho-p53, and Mdm2 levels in human tumors, supporting the role of this path in tumorigenesis. Our findings introduce the concept that RTK-driven tumors may be therapeutically treated by hitting signaling nodes interconnecting core pathways. Moreover, they underline the importance of evaluating the relevance of c-Abl antagonists for combined therapies, based on the tumor signaling signature.Cell Death and Differentiation advance online publication, 1 April 2011; doi:10.1038/cdd.2011.23

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Coactivation of Receptor Tyrosine Kinases Affects the Response of Tumor Cells to Targeted Therapies

Cited by 824 publications

References 16 publications

AXL regulates mesothelioma proliferation and invasiveness

AXL regulates mesothelioma proliferation and invasiveness

EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function

Abl interconnects oncogenic Met and p53 core pathways in cancer cells

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