Abstract
BackgroundAberrant 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.MethodsUsing 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.ResultsPatients 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).ConclusionsPI3K 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.
Highlights
Aberrant PI3K signalling is implicated in trastuzumab resistance in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC)
We investigated whether targeting the PI3K or MAPK pathway in vitro using copanlisib, a p110α/δ inhibitor, or refametinib, a MEK1/2 inhibitor, could potentially improve responses to anti-HER therapies in HER2-positive GCs and provide evidence to support a future Phase Ib clinical trial
These inhibitors were chosen as we have previously shown that copanlisib and refametinib can restore sensitivity to anti-HER2 therapies in vitro in HER2-positive breast cancer cell lines with acquired resistance to trastuzaumab and lapatinib, we hypothesised that we would observe a similar effect in HER2-positive GC cell lines [24, 25]
Summary
Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). Median survival is approximately 9 months in patients treated with chemotherapy compared with 5 months for patients treated with supportive care alone [5]. The phase III ToGA (Trastuzumab for Gastric Cancer) trial investigated the role of trastuzumab therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. The addition of trastuzumab led to an increase in overall survival by 2.7 months compared to chemotherapy alone [8]. This led to the approval of trastuzumab as the first molecular targeted therapy for GC, not all patients with HER2-positive GC respond to trastuzumab, and the majority of patients who respond develop resistance after a relatively short period of time [15]. The identification of mechanisms underlying treatment resistance could potentially identify novel treatment options to improve trastuzumab sensitivity in HER2-positive GC
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