Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in Glioblastoma

Inan Olmez, Ying Zhang, Laryssa Manigat, Mouadh Benamar, Breanna Brenneman, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Jeongwu Lee, Tarek Abbas, Roger Abounader, Benjamin Purow

Research output: Contribution to journalArticlepeer-review

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Abstract

Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-kB-mediated upregulation of hepatocyte growth factor, brain-derived neurotrophic factor, and nerve growth factor that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c- Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials.

Original languageEnglish (US)
Pages (from-to)4360-4369
Number of pages10
JournalCancer Research
Volume78
Issue number15
DOIs
StatePublished - Aug 1 2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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