Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Using mass spectrometry-based genotyping we analysed 105 hotsp...

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Bibliographic Details
Published in:	Journal of translational medicine Vol. 19; no. 1; p. 184
Main Authors:	Mezynski, M Janusz, Farrelly, Angela M, Cremona, Mattia, Carr, Aoife, Morgan, Clare, Workman, Julie, Armstrong, Paul, McAuley, Jennifer, Madden, Stephen, Fay, Joanna, Sheehan, Katherine M, Kay, Elaine W, Holohan, Ciara, Elamin, Yasir, Rafee, Shereen, Morris, Patrick G, Breathnach, Oscar, Grogan, Liam, Hennessy, Bryan T, Toomey, Sinead
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 01-05-2021 BioMed Central BMC
Subjects:	1-Phosphatidylinositol 3-kinase Antibodies Cancer Cancer therapies Care and treatment Chemotherapy Development and progression Drug resistance Drug therapy Epidermal growth factor receptors ErbB protein ErbB-2 protein ErbB-3 protein Gastric cancer Genetic aspects Genotyping Growth inhibition Health aspects HER2-positive gastric cancer Kinases MAP kinase MAPK Mass spectroscopy Medical prognosis MEK inhibitors Metastasis Mutation Patients Physiological aspects PI3K Protein kinases Proteins Signal transduction Signalling pathway activation Somatic mutations Stomach cancer Targeted therapies Trastuzumab Tumors Ireland United States > US Targeted therapies HER2-positive gastric cancer Treatment resistance PI3K Somatic mutations MAPK Signalling pathway activation
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Summary:	Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM-1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1479-5876 1479-5876
DOI:	10.1186/s12967-021-02842-1