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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
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Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase
Dietrich A Ruess1,2, Guus J Heynen3, Katrin J Ciecielski1
1Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Nature Medicine
|May 30, 2018
Summary
SHP2 is essential for KRAS-driven cancers. Combining SHP2 and MEK inhibitors offers a promising targeted therapy for pancreatic and lung cancers, improving tumor growth control.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- SHP2 (PTPN11) is a protein tyrosine phosphatase crucial for signaling pathways.
- SHP2 is implicated in oncogenic signaling but its role in KRAS-mutant cancers was unclear.
- Previous SHP2 inhibitors were ineffective against KRAS-mutant tumors.
Purpose of the Study:
- To investigate the role of SHP2 in oncogenic KRAS-driven tumors.
- To evaluate the therapeutic potential of targeting SHP2 in KRAS-mutant cancers.
- To explore combination therapies involving SHP2 and MEK inhibition.
Main Methods:
- Genetic deletion of Ptpn11 in murine models of pancreatic ductal adenocarcinoma (PDAC) and non-small-cell lung cancer (NSCLC).
- Inhibition of SHP2 and MEK in established tumors, organoids, and xenograft models.
- Assessment of tumor development, progression, and resistance mechanisms.
Main Results:
- SHP2 is indispensable for KRAS-driven tumor development and progression.
- SHP2 deletion or inhibition delayed tumor growth but did not cause regression.
- SHP2 is critical for resistance to MEK blockade; dual SHP2/MEK inhibition achieved sustained tumor control.
Conclusions:
- SHP2 plays a central role in KRAS-driven oncogenesis.
- Targeting SHP2 is a viable strategy for KRAS-mutant cancers.
- Combined SHP2 and MEK inhibition demonstrates significant therapeutic potential for PDAC and NSCLC.
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