SHP2 Inhibition Overcomes RTK-Mediated Pathway Reactivation in KRAS-Mutant Tumors Treated with MEK Inhibitors

DOI PDF 被引用文献3件
  • Hengyu Lu
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Chen Liu
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Roberto Velazquez
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Hongyun Wang
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Lukas Manuel Dunkl
    2Novartis Institutes for BioMedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland.
  • Malika Kazic-Legueux
    2Novartis Institutes for BioMedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland.
  • Anne Haberkorn
    2Novartis Institutes for BioMedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland.
  • Eric Billy
    2Novartis Institutes for BioMedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland.
  • Eusebio Manchado
    2Novartis Institutes for BioMedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland.
  • Saskia M. Brachmann
    2Novartis Institutes for BioMedical Research, Oncology Disease Area, Novartis Pharma AG, Basel, Switzerland.
  • Susan E. Moody
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Jeffrey A. Engelman
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Peter S. Hammerman
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Giordano Caponigro
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Morvarid Mohseni
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.
  • Huai-Xiang Hao
    1Novartis Institutes for BioMedical Research, Oncology Disease Area, Cambridge, Massachusetts.

説明

<jats:title>Abstract</jats:title> <jats:p>FGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with the MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTK) are also feedback-activated in this context. Herein, we profile a large panel of KRAS-mutant cancer cell lines for the contribution of RTKs to the feedback activation of phospho-MEK following MEK inhibition, using an SHP2 inhibitor (SHP099) that blocks RAS activation mediated by multiple RTKs. We find that RTK-driven feedback activation widely exists in KRAS-mutant cancer cells, to a less extent in those harboring the G13D variant, and involves several RTKs, including EGFR, FGFR, and MET. We further demonstrate that this pathway feedback activation is mediated through mutant KRAS, at least for the G12C, G12D, and G12V variants, and wild-type KRAS can also contribute significantly to the feedback activation. Finally, SHP099 and MEK inhibitors exhibit combination benefits inhibiting KRAS-mutant cancer cell proliferation in vitro and in vivo. These findings provide a rationale for exploration of combining SHP2 and MAPK pathway inhibitors for treating KRAS-mutant cancers in the clinic.</jats:p>

収録刊行物

被引用文献 (3)*注記

もっと見る

詳細情報 詳細情報について

問題の指摘

ページトップへ