Abstract
Receptor tyrosine kinases (RTKs) are recognized as targets of precision medicine in human cancer upon their gene amplification or constitutive activation, resulting in increased downstream signal complexity including heterotypic crosstalk with other RTKs. The Met RTK exhibits such reciprocal crosstalk with several members of the human EGFR (HER) family of RTKs when amplified in cancer cells. We show that Met signaling converges on HER3–tyrosine phosphorylation across a panel of seven MET-amplified cancer cell lines and that HER3 is required for cancer cell expansion and oncogenic capacity in vitro and in vivo. Gene expression analysis of HER3-depleted cells identified MPZL3, encoding a single-pass transmembrane protein, as HER3-dependent effector in multiple MET-amplified cancer cell lines. MPZL3 interacts with HER3 and MPZL3 loss phenocopies HER3 loss in MET-amplified cells, while MPZL3 overexpression can partially rescue proliferation upon HER3 depletion. Together, these data support an oncogenic role for a HER3–MPZL3 axis in MET-amplified cancers.
Highlights
Receptor tyrosine kinases (RTKs) have been among the earliest and most effective targets for precision medicine in human cancer [1]
To establish whether Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2) or HER3 phosphorylation is dependent on Met activity in our panel, we treated the panel of cell lines for one hour with PHA-665752 (PHA) a smallmolecule tyrosine kinase inhibitor highly selective for Met over EGFR and HER2 at sub-micromolar concentrations, at 0.5 μM [33, 34]
While EGFR and HER2 were basally tyrosine phosphorylated in all cell lines tested, tyrosine phosphorylation of EGFR was dependent on Met kinase activity in three out of seven tested cell lines (OE33, EBC1 and H1993) and tyrosine phosphorylation of HER2 was dependent on Met activity in two lung cancer cell lines tested (EBC1 and H1993) (Fig. 1b)
Summary
Receptor tyrosine kinases (RTKs) have been among the earliest and most effective targets for precision medicine in human cancer [1]. RTK activation canonically proceeds through receptor homo-oligomerization and trans-autophosphorylation, but many cases of heterotypic signaling between different RTKs, frequently referred to as crosstalk, have been reported in the literature [2, 3]. Epidermal growth factor receptor (EGFR)-family RTKs in particular have become targets for clinical intervention in human cancer. The EGFR family contains four paralogous receptor tyrosine kinases that evolved from a single-precursor EGFR homologue and exhibits extensive crosstalk with each other [1]. EGFR, human epidermal growth factor receptor 2 (HER2) and HER3 are frequently overexpressed in human cancers and have been shown to induce canonical cancer-associated signals upon their activation by mutation, gene amplification or constitutive ligand presentation [1, 4]. These interventions are part of the standard of care in lung, breast, and colorectal cancer therapy [5, 6]
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