SHP2 Inhibition Overcomes RTK-Mediated Pathway Reactivation in KRAS-Mutant Tumors Treated with MEK Inhibitors
-
- 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
-
- Molecular Cancer Therapeutics
-
Molecular Cancer Therapeutics 18 (7), 1323-1334, 2019-07-01
American Association for Cancer Research (AACR)
