Novel preclinical patient-derived lung cancer models reveal inhibition of HER3 and MTOR signaling as therapeutic strategies for NRG1 fusion-positive cancers Journal Article


Authors: Odintsov, I.; Mattar, M. S.; Lui, A. J. W.; Offin, M.; Kurzatkowski, C.; Delasos, L.; Khodos, I.; Asher, M.; Daly, R. M.; Rekhtman, N.; de Stanchina, E.; Ganji, G.; Ladanyi, M.; Somwar, R.
Article Title: Novel preclinical patient-derived lung cancer models reveal inhibition of HER3 and MTOR signaling as therapeutic strategies for NRG1 fusion-positive cancers
Abstract: Introduction: NRG1 rearrangements produce chimeric ligands that subvert the ERBB pathway to drive tumorigenesis. A better understanding of the signaling networks that mediate transformation by NRG1 fusions is needed to inform effective therapeutic strategies. Unfortunately, this has been hampered by a paucity of patient-derived disease models that faithfully recapitulate this molecularly defined cancer subset. Methods: Patient-derived xenograft (PDX) and cell line models were established from NRG1-rearranged lung adenocarcinoma samples. Transcriptomic, proteomic, and biochemical analyses were performed to identify activated pathways. Efficacy studies were conducted to evaluate HER3- and MTOR-directed therapies. Results: We established a pair of PDX and cell line models of invasive mucinous lung adenocarcinoma (LUAD) (LUAD-0061AS3, SLC3A2-NRG1), representing the first reported paired in vitro and in vivo model of NRG1-driven tumors. Growth of LUAD-0061AS3 models was reduced by the anti-HER3 antibody GSK2849330. Transcriptomic profiling revealed activation of the MTOR pathway in lung tumor samples with NRG1 fusions. Phosphorylation of several MTOR effectors (S6 and 4EBP1) was higher in LUAD-0061AS3 cells compared with human bronchial epithelial cells and the breast cancer cell line MDA-MB-175-VII (DOC4-NRG1 fusion). Accordingly, LUAD-0061AS3 cells were more sensitive to MTOR inhibitors than MDA-MB-175-VII cells and targeting the MTOR pathway with rapamycin blocked growth of LUAD-0061AS3 PDX tumors in vivo. In contrast, MDA-MB-175-VII breast cancer cells had higher MAPK pathway activation and were more sensitive to MEK inhibition. Conclusions: We identify the MTOR pathway as a candidate vulnerability in NRG1 fusion-positive lung adenocarcinoma that may warrant further preclinical evaluation, with the eventual goal of finding additional therapeutic options for patients in whom ERBB-directed therapy fails. Moreover, our results uncover heterogeneity in downstream oncogenic signaling among NRG1-rearranged cancers, possibly tumor type-dependent, the therapeutic significance of which requires additional investigation. © 2021
Keywords: lung adenocarcinoma; nrg1 fusion; gsk2849330; her3 antibody
Journal Title: Journal of Thoracic Oncology
Volume: 16
Issue: 7
ISSN: 1556-0864
Publisher: Elsevier Inc.  
Date Published: 2021-07-01
Start Page: 1149
End Page: 1165
Language: English
DOI: 10.1016/j.jtho.2021.03.013
PUBMED: 33839363
PROVIDER: scopus
PMCID: PMC9261529
DOI/URL:
Notes: Article -- Export Date: 2 August 2021 -- Source: Scopus
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MSK Authors
  1. Natasha Rekhtman
    424 Rekhtman
  2. Marc Ladanyi
    1326 Ladanyi
  3. Romel Somwar
    110 Somwar
  4. Marina Asher
    36 Asher
  5. Lukas   Delasos
    14 Delasos
  6. Inna   Khodos
    36 Khodos
  7. Marissa   Mattar
    56 Mattar
  8. Michael David Offin
    170 Offin
  9. Robert M Daly
    78 Daly
  10. Jo Weng Allan Lui
    15 Lui