Author of

• 17629

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  P2.03b - Poster Session with Presenters Present (ID 465)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 17700

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    P2.03b-071 - Therapeutic Targeting of the Phosphatidylinositol-3 Kinase Pathway in Lung Squamous Cell Carcinoma (ID 5369)

    14:30 - 14:30  |  Author(s): N. Moghal
    • Abstract

    Background:
    The phosphatidylinositol-3 kinase (PI3K) belongs to a family of lipid kinases involved in the regulation of cell proliferation and survival and is often dysregulated in cancer. Comprehensive molecular profiling by The Cancer Genome Atlas (TCGA) has identified PIK3CA mutations, amplifications, and the tumor suppressor PTEN loss in 30-40% of lung squamous cell carcinoma (LUSC) patients. Inhibitors of PI3K such as BKM120 have been initiated in BASALT-1 trial (NCT01820325) of PI3K activated LUSC, however with modest response rate (40% of patients with stable disease and 3.3% with partial response). We aim to assess the efficacy of PI3K inhibition in LUSC patient-derived xenografts (PDX) harboring different PI3K pathway alterations to identify potential mechanisms of innate resistance.
    
    Methods:
    PDX models were established from early stage LUSC patients and molecularly characterized via exome sequencing, SNP array for copy number variation (CNV) and gene expression analysis. PIK3CA mutations were validated by direct sequencing, amplifications by fluorescence in situ hybridization (FISH), and PTEN loss by immunohistochemistry (IHC). For in vivo drug screening, each PDX model was implanted in two mice; one treated with BKM120 (50mg/kg) and the other with vehicle control by daily oral gavage. Tumors were monitored twice weekly with caliper measurement. A responder is a tumor that regresses completely, shrinks more than 30%, or remains a stable size according to the RECIST criteria.
    
    Results:
    Of the 75 LUSC PDX models that our laboratory has established, 11 (14%) harbored PIK3CA E545K and E542K mutations, 36 (47%) harbored PIK3CA amplifications, and 23 (30%) showed loss of PTEN protein expression. Using the RECIST criteria, BKM120 screening in selected PDX models revealed stable disease and progressive disease in 4/9 (46%) and 5/9 (54%) of the PDX models, respectively, after 21 days of treatment. Of the 9 PDX models tested, 3/5 PIK3CA mutant models were responsive to BKM120, whereas none of the other 4 PIK3CA amplified and/or PTEN deleted models were responsive to BKM120. Additionally, downregulation of pErk1/2 and pS6 in a responder model and no change in phosphorylated proteins in non-responding models were observed. Pharmacodynamics studies, validation of responders with more mouse replicates, and testing on the remaining models are ongoing and the results will be reported.
    
    Conclusion:
    60% of LUSC PDXs with PIK3CA mutation demonstrate high sensitivity to pan-PI3K inhibitor. Understanding innate resistance mechanisms of PI3K inhibition may provide important insights on tractable targets and therapeutic strategy for LUSC patients with aberrant PI3K pathway.