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Martin Frederik Dietrich



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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.01 - Cbl Mutations (mt) as Important Mediators of Oncogenic RTK Signaling in NSCLC (ID 12377)

      15:15 - 15:20  |  Author(s): Martin Frederik Dietrich

      • Abstract
      • Presentation
      • Slides

      Background

      Casitas B-lineage lymphoma (Cbl), an E3 ubiquitin ligase, selectively regulates receptor tyrosine kinase (RTKs), e.g. EGFR, MET. Cbl loss of function (LOF) mt can can prevent ubiquitination of EGFR and potentiate EGFR signaling. Cbl mt have been described in cases of EGFR-TKI resistance but because EGFR signaling can activate signaling of fusion kinases and other ERBB family members, the implications of Cbl mt warrant broad characterization

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Biopsies from NSCLC pts tested with Next-Generation Sequencing on a 592-gene panel (Illumina NextSeq, ArcherDx) were analyzed retrospectively. Cbl domains of interest: LOF [tyrosine kinase binding (TKB), linker (L), ring finger (RF) and ubiquitin-associated (UBA)] and unclear function [N-terminal (NT) and proline-rich (PR)]. Chi-square analysis was used to compare co-alteration rates.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 4,484 NSCLC pts’ tumors (50% M/50% F; age range: 20-90, profiled 11/16-12/17), 222 had Cbl mt (5%), of which 65 (29% of mt, 1.4% of cohort) were LOF: 13% TKB (29), 7% L (15), 5% RF (13), and 3.6% UBA (8). Cbl LOF mt were primarily observed in adenocarcinomas (48/65), metastatic sites (35/65) and equal between M/F. Cbl mt in other domains: 23% PR (51) and 14% NT (31). Co-mutation distribution is shown in table below. Cbl LOF mt that disrupt Cbl function (H398N, S407C, C396R, Y371D, T377I/H) or interactions w/ RTK (S216G, P288S, F325L) co-occurred w/ oncogenes in nine pts: EGFR (L858R, S768I, exon19del+T790M), ERBB3 (V104M, G284R), EML4-ALK (n = 2), CD74-ROS1 (n = 1), and HER2 (D1125E).

      LOF

      WT

      Oncogene

      pos/total (%)

      P

      ERBB3 mt

      2/65 (3.1)

      6/4329 (0.1)

      < 0.001

      EGFR mt

      3/65 (4.6)

      491/4329 (11.3)

      0.08

      METex14

      0/65 (0)

      100/4329 (2.3)

      0.2

      ROS

      1/60 (1.7)

      22/3976 (0.6)

      0.2

      KRAS mt

      14/65 (21)

      1242/3086 (29)

      0.2

      BRAF V600E

      0/65 (0)

      56/4312 (1.3)

      0.3

      ALK

      2/60 (3.3)

      97/4175 (2.3)

      0.6

      ERBB4 mt

      0/65 (0)

      6/4329 (0.1)

      0.7

      HER2 mt

      1/65 (1.5)

      58/4328 (1.3)

      0.9
      8eea62084ca7e541d918e823422bd82e Conclusion

      Regulation of RTK signaling through Cbl-mediated degradative pathways represents an important node for dysregulation in cancer. Presence of Cbl LOF mt in oncogene-driven tumors may provide a bypass signaling-enabled molecular landscape. Further analysis of the role of Cbl LOF mt in de-novo or acquired TKI resistance in pts identified is planned.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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