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Kinase inhibitors of HER2/AKT pathway induce ERK phosphorylation via a FOXO-dependent feedback loop.

ABSTRACT: Inhibitors of the HER2/PI3K/AKT pathway are being developed, and shown promise in clinical trials for various types of cancers. However, development of drug resistance is a challenging problem for therapy. Elucidating various adaptive pathways leading to resistance or reduced sensitivity to drugs targeting the HER2/PI3K/AKT pathway may provide new insights into countering the resistance. Epidermal growth factor receptor (EGFR, aka HER1), which can dimerize with HER2, can activate a cascade consisting of Ras/RAF/MEK/ERK, promoting tumorigenesis. Lapatinib inhibits the kinase activity of both HER1 and HER2. In the current study, we found that repeated treatment of HER2+ breast cancer cells with HER1/2 inhibitor Lapatinib led to increased phosphorylation of RAF, MEK, and ERK, while suppressing HER1 phosphorylation and reduced the active form of Ras, indicating existence of factor(s) activating RAF/MEK/ERK by bypassing RAS activation. Notably, the Lapatinib treatment-induced phosphorylation of ERK was dependent on FOXO transcription factors, which are also activated by Lapatinib-mediated suppression of AKT. Moreover, the Lapatinib-induced phosphorylation of RAF and ERK is inhibited by a pan-PKC inhibitor. Furthermore, the Lapatinib induced increased ERK phosphorylation is correlated with increased stability of c-Myc, which is known to be stabilized by ERK-mediated phosphorylation. Together, these results suggest that chronic inhibition of the HER1/2 by Lapatinib triggers a feedback loop to activate RAF/MEK/ERK pathway, in a FOXO dependent but Ras-independent manner.

SUBMITTER: Matkar S

PROVIDER: S-EPMC5523029 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Kinase inhibitors of HER2/AKT pathway induce ERK phosphorylation via a FOXO-dependent feedback loop.

Matkar Smita S An Chiying C Hua Xianxin X

American journal of cancer research 20170701 7

Inhibitors of the HER2/PI3K/AKT pathway are being developed, and shown promise in clinical trials for various types of cancers. However, development of drug resistance is a challenging problem for therapy. Elucidating various adaptive pathways leading to resistance or reduced sensitivity to drugs targeting the HER2/PI3K/AKT pathway may provide new insights into countering the resistance. Epidermal growth factor receptor (EGFR, aka HER1), which can dimerize with HER2, can activate a cascade consi ...[more]

PMID: 28744398

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Project description:Herceptin (trastuzumab) is used in patients with breast cancer who have HER2 (ErbB2)-positive tumours. However, its mechanisms of action and how acquired resistance to Herceptin occurs are still poorly understood. It was previously thought that the anti-HER2 monoclonal antibody Herceptin inhibits HER2 signalling, but recent studies have shown that Herceptin does not decrease HER2 phosphorylation. Its failure to abolish HER2 phosphorylation may be a key to why acquired resistance inevitably occurs for all responders if Herceptin is given as monotherapy. To date, no studies have explained why Herceptin does not abolish HER2 phosphorylation. The objective of this study was to investigate why Herceptin did not decrease HER2 phosphorylation despite being an anti-HER2 monoclonal antibody. We also investigated the effects of acute and chronic Herceptin treatment on HER3 and PKB phosphorylation in HER2-positive breast cancer cells. Using both Förster resonance energy transfer (FRET) methodology and conventional Western blot, we have found the molecular mechanisms whereby Herceptin fails to abolish HER2 phosphorylation. HER2 phosphorylation is maintained by ligand-mediated activation of EGFR, HER3, and HER4 receptors, resulting in their dimerisation with HER2. The release of HER ligands was mediated by ADAM17 through a PKB negative feedback loop. The feedback loop was activated because of the inhibition of PKB by Herceptin treatment since up-regulation of HER ligands and ADAM17 also occurred when PKB phosphorylation was inhibited by a PKB inhibitor (Akt inhibitor VIII, Akti-1/2). The combination of Herceptin with ADAM17 inhibitors or the panHER inhibitor JNJ-26483327 was able to abrogate the feedback loop and decrease HER2 phosphorylation. Furthermore, the combination of Herceptin with JNJ-26483327 was synergistic in tumour inhibition in a BT474 xenograft model. We have determined that a PKB negative feedback loop links ADAM17 and HER ligands in maintaining HER2 phosphorylation during Herceptin treatment. The activation of other HER receptors via ADAM17 may mediate acquired resistance to Herceptin in HER2-overexpressing breast cancer. This finding offers treatment opportunities for overcoming resistance in these patients. We propose that Herceptin should be combined with a panHER inhibitor or an ADAM inhibitor to overcome the acquired drug resistance for patients with HER2-positive breast cancer. Our results may also have implications for resistance to other therapies targeting HER receptors.

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Dataset Information

Kinase inhibitors of HER2/AKT pathway induce ERK phosphorylation via a FOXO-dependent feedback loop.

Publications

Kinase inhibitors of HER2/AKT pathway induce ERK phosphorylation via a FOXO-dependent feedback loop.

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