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J. Amann



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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.05 - Oncogenic ARAF mutation in lung adenocarcinoma (ID 2860)

      16:15 - 17:45  |  Author(s): J. Amann

      • Abstract
      • Presentation
      • Slides

      Background
      Targeted cancer therapies often induce “outlier” responses in molecularly defined patient subsets.

      Methods
      One patient with advanced-stage lung adenocarcinoma, who was treated with oral sorafenib, demonstrated a complete clinical and radiographic remission for five years. Whole genome sequencing (WGS) and RNA sequencing (RNA-seq) on primary tumor and normal samples from this patient was performed.

      Results
      We identified a somatic mutation, ARAF S214C, present in the cancer genome and expressed at high levels. Additional mutations affecting this residue of ARAF and a nearby residue in the related kinase RAF1 were demonstrated across 1% of an independent cohort of lung adenocarcinoma cases. The ARAF mutants were shown to transform immortalized human airway epithelial cells and were associated with in vitro sorafenib sensitivity.

      Conclusion
      These results suggest that mutant ARAF may be a novel oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-025 - EGFR blockade increases lung cancer stem cell-like cells by upregulation of Notch3 signaling. (ID 3487)

      09:30 - 16:30  |  Author(s): J. Amann

      • Abstract

      Background
      Blockade of genetic driver alterations in cell signaling pathways such as the epidermal growth factor receptor (EGFR) have led to dramatic tumor responses in the metastatic setting. However, these agents have unexpectedly failed to improve outcomes in clinical trails of early stage (BR.19) and locally advanced (S0023) NSCLC. In fact, survival was significantly worse among patients receiving gefitinib in the S0023 trial, and trended to be worse in BR.19. While it is clear that EGFR TKIs can reduce the tumor bulk and improve symptoms in the metastatic setting, these results raise the possibility that EGFR inhibition might somehow stimulate tumor growth either directly or indirectly.

      Methods
      We studied the fractions and numbers of ALDH+ cells and activation of stemcell signaling pathways in two EGFR mutated cell lines treated with erlotinib.

      Results
      Here, we report that treatment of EGFR-mutated lung cancer cell lines with erlotinib, while showing robust cell death, essentially increases the fraction and absolute number of ALDH+ clonogenic stem cell-like cells. This phenomenon can be abolished by inhibition of Notch3, while Notch1 inhibition has little effect or slightly increases ALDH+ cells. We demonstrate EGFR kinase activity-dependent coprecipitation of Notch and EGFR receptors and EGFR kinase dependent tyrosine phosphorylation of the Notch3 receptor. We further found that inhibition of EGFR activity leads to increased nuclear accumulation of gamma-secretase dependent Notch3 that correlates with the increase in ALDH+ cells.

      Conclusion
      These data suggest that while EGFR TKIs are very effective at debulking tumors in the metastatic setting, inhibition of EGFR paradoxically causes Notch activation and an increase in clonogenic stem cell-like cells. Therefore, curative-intent therapy may be best accomplished by dual targeting of EGFR and Notch3.

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-017 - LKB1 loss induces characteristic pathway activation in human tumors and confers sensitivity to MEK inhibition due to attenuated PI3K-AKT-FOXO3 signaling. (ID 2847)

      09:30 - 16:30  |  Author(s): J. Amann

      • Abstract

      Background
      Inactivation of STK11/LKB1 is one of the most common genetic events in lung cancer, and understanding the cellular phenotypes and molecular pathways altered as a consequence will aid the development of therapeutic strategies targeting LKB1-deficient cancers.

      Methods
      We report the comprehensive analysis of gene and protein expression patterns associated with LKB1 loss in lung adenocarcinomas, through which we identify hallmarks of altered tumor metabolism and down-regulation of the PI3K/AKT pathway.

      Results
      Significant differences are observed between human tumors and those derived from a genetically engineered mouse model of LKB1 loss. A 16-gene signature is predictive of both mutational and non-mutational LKB1 loss in human tumors. Cell lines expressing this signature show increased sensitivity to MEK inhibition, independent of mutations in RAS and RAF family members. Restoration of LKB1 in lung cancer cell lines down-regulates the gene expression pattern, attenuates FOXO3, and induces resistance to MEK inhibition.

      Conclusion
      These findings identify characteristic phenotypic features of LKB1-deficient tumors and identify LKB1 loss as a novel determinant of MEK sensitivity.