Virtual Library

Start Your Search

W. Holland

Author of

  • +

    MO20 - Preclinical Therapeutic Models II (ID 93)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • +

      MO20.04 - Divergent activity of afatinib (AFAT) and cetuximab (CET) in patient-derived xenograft (PDX) models of acquired erlotinib resistance. (ID 1458)

      10:30 - 12:00  |  Author(s): W. Holland

      • Abstract
      • Presentation
      • Slides

      The combination of AFAT and CET has demonstrated remarkable clinical activity in patients with acquired resistance to erlotinib. Preclinical modeling in genetically engineered mice and cell lines predicted activity in cases where erlotinib resistance was mediated by the EGFR T790M gatekeeper mutation. However, in the clinic, patients lacking T790M-positive tumors showed equivalent benefit from this combination, suggesting alternative mechanisms of synergy. We explored the individual and combined molecular and growth inhibitory activity of these agents in PDX models derived from NSCLC patient tumors with distinct mechanisms of acquired resistance to erlotinib. These models were developed by the UC Davis - Jackson Laboratories Consortium, which has xenotransplanted over 170 NSCLC models using the nod/scid/IL2Rgamma chain-null (NSG) mouse.

      EGFR-mutant PDX models LG0703 (T790M-negative) and LG1049 (T790M-positive) were established from tumor biopsies from patients who progressed following durable responses to erlotinib. Both patients were subsequently treated with AFAT+CET, with the LG0703 donor patient exhibiting a prolonged response and the LG1049 donor patient exhibiting a transient response followed by rapid progression. Excised tumors from passage 1 PDXs were fragmented and implanted into treatment cohorts. When tumors reached 300mm[3], mice were randomized to erlotinib (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. In a parallel cohort, tumor pharmacodynamic changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting.

      In LG0703, AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period. After cessation of treatment, mice treated with CET or AFAT-CET remained in complete remission; whereas AFAT-treated mice progressed within 2 weeks. Clinical activity in this model was associated with complete blockade of EGFR and Her2 phosphorylation. Substantial down-regulation of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K phosphorylation was evident within 6h of treatment. In contrast, the T790M-postive LG1049 model demonstrated only modest clinical benefit from AFAT, with no single-agent CET activity, and no CET-mediated synergy with AFAT. No treatments were able to ablate EGFR phosphorylation or downstream signal transduction, and compensatory induction of EGFR, HER2, ERK1 and p38 were noted after 24h of drug exposure.

      In these PDX models derived from patients with EGFR-activating mutant cancer with acquired resistance to erlotinib, treatment with AFAT+CET recapitulated the clinical experience of the donor patients receiving this combination. In the LG0703 model, both the AFAT-CET combination as well as single-agent CET resulted in complete tumor regression associated with total ablation of EGFR phosphorylation and subsequent blockade of multiple signal transduction pathways. In the LG1049 model, AFAT prompted limited but statistically significant tumor delay, with no additional benefit from CET. These experiments demonstrate the considerable potential of this PDX resource to assess therapeutic strategies in models representing individual patients. Supported by BJALCF.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.