Person:
Ivanova, Elena

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Ivanova

First Name

Elena

Name

Ivanova, Elena

Filters

20122

Settings

Author's Publications: search.filters.isAuthorOfPublication.af5d52e0-a46b-4ddf-9013-090b4b3e50ef

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Publication
    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.
  • Thumbnail Image
    Publication
    Melanoma genome sequencing reveals frequent PREX2 mutations
    (2012) Berger, Michael F.; Hodis, Eran; Heffernan, Timothy P.; Deribe, Yonathan Lissanu; Lawrence, Michael S.; Protopopov, Alexei; Ivanova, Elena; Watson, Ian; Nickerson, Elizabeth; Ghosh, Papia; Zhang, Hailei; Zeid, Rhamy; Ren, Xiaojia; Cibulskis, Kristian; Sivachenko, Andrey Y.; Wagle, Nikhil; Sucker, Antje; Sougnez, Carrie; Onofrio, Roberto; Ambrogio, Lauren; Auclair, Daniel; Fennell, Timothy; Carter, Scott L.; Drier, Yotam; Stojanov, Petar; Singer, Meredith A.; Voet, Douglas; Jing, Rui; Saksena, Gordon; Barretina, Jordi; Ramos, Alex H.; Pugh, Trevor J.; Stransky, Nicolas; Parkin, Melissa Ann; Winckler, Wendy; Mahan, Scott; Ardlie, Kristin; Baldwin, Jennifer; Wargo, Jennifer Ann; Schadendorf, Dirk; Meyerson, Matthew; Gabriel, Stacey B.; Golub, Todd; Wagner, Stephan N.; Lander, Eric; Getz, Gad; Chin, Lynda; Garraway, Levi
    Melanoma is notable for its metastatic propensity, lethality in the advanced setting, and association with ultraviolet (UV) exposure early in life1. To obtain a comprehensive genomic view of melanoma, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-UV exposed hairless skin of the extremities (3 and 14 per Mb genome), intermediate in those originating from hair-bearing skin of the trunk (range = 5 to 55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 - a PTEN-interacting protein and negative regulator of PTEN in breast cancer2 - as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumor formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumors revealed genomic evidence of UV pathogenesis and discovered a new recurrently mutated gene in melanoma.