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Xu, Chunxiao

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Xu

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Chunxiao

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Xu, Chunxiao
Author's Publications: search.filters.isAuthorOfPublication.b757d377-e249-4793-8848-6066a8725695

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    RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS
    (2014) Cottini, Francesca; Hideshima, Teru; Xu, Chunxiao; Sattler, Martin; Dori, Martina; Agnelli, Luca; Hacken, Elisa ten; Bertilaccio, Maria Teresa; Antonini, Elena; Neri, Antonino; Ponzoni, Maurilio; Marcatti, Magda; Richardson, Paul; Carrasco, Ruben; Kimmelman, Alec C.; Wong, Kwok-Kin; Caligaris-Cappio, Federico; Blandino, Giovanni; Kuehl, W. Michael; Anderson, Kenneth; Tonon, Giovanni
    Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.
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    Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors
    (American Association for Cancer Research (AACR), 2012) Ercan, Dalia; Xu, Chunxiao; Yanagita, Masahiko; Monast, Calixte S.; Pratilas, Christine A.; Montero, Juan; Butaney, Mohit; Shimamura, Takeshi; Sholl, Lynette; Ivanova, Elena; Tadi, Madhavi; Rogers, Andrew; Repellin, Claire; Capelletti, Marzia; Maertens, Ophelia; Goetz, Eva Marie; Letai, Anthony; Garraway, Levi; Lazzara, Matthew J.; Rosen, Neal; Gray, Nathanael; Wong, Kwok-Kin; Janne, Pasi
    The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib resistant EGFR mutant NSCLC patient. In addition, the WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rationale combination therapies that should be evaluated in clinical trials.