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

Mezynski, M Janusz
; 
Farrelly, Angela M
; 
Cremona, Mattia
; 
Carr, Aoife
; 
Morgan, Clare
; 
Workman, Julie
; 
Armstrong, Paul
; 
McAuley, Jennifer
; 
Madden, Stephen
; 
Fay, Joanna
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Author
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
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Date
2021-05-01
Date Submitted
Keywords
HER2-positive gastric cancer
MAPK
PI3K
Signalling pathway activation
Somatic mutations
Targeted therapies
Treatment resistance
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s12967-021-02842-1.pdf
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https://hdl.handle.net/10147/631562
Abstract
Background: 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. Methods: 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. Results: 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). Conclusions: 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.
Language
en
Citation
ISSN
eISSN
1479-5876
ISBN
DOI
10.1186/s12967-021-02842-1
PMID
33933113
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