HER2 is overexpressed in 10-25% of gastric cancers (GCs). The association of PI3K pathway activating mutations with HER2 overexpression, or the impact of aberrant PI3K pathway signalling on response to trastuzumab (Tr) in GC has not been described. In HER2-positive breast cancer, targeting the PI3K pathway can overcome resistance to HER2-targeted therapies; however the role of PI3K inhibitors in sensitizing HER2-positive GCs to Tr or in overcoming Tr resistance is unknown.
Tumour samples from 69 GC patients were stratified into HER2-positive (n = 29) and HER2-negative (n = 40) groups. Mass spectrometry-based genotyping (Agena Bioscience) was used to analyse 105 hotspot somatic mutations in PIK3CA, EGFR, ERBB2, ERBB3 and ERBB4 in the tumours and in a panel of HER2-positive GC cell lines (N87, OE19, ESO26 and SNU16). The anti-proliferative response to the PI3K inhibitor copanlisib alone and in combination with the HER2-targeted therapies Tr and lapatinib was assessed in vitro.
Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months; p = 0.0032). PIK3CA, EGFR and ERBB mutations occurred more frequently in HER2-negative tumours than HER2-positive tumours, but had no impact on progression free or overall survival. In vitro OE19 cells were resistant to copanlisib, while all other cell lines were sensitive, independent of PIK3CA mutation status, with IC50s ranging from 23.4nm (N87) to 93.8nm (SNU16). All cell lines except SNU16 were sensitive to lapatinib with IC50s ranging from 0.04µM to 1.5µM. OE19 and SNU16 were resistant to Tr. The combination of lapatinib and copanlisib is synergistic in ESO-26 and OE-19 cells (ED50: 0.83±0.19 and 0.88±0.13, respectively) and additive in N87 cells (ED50:1.01±0.55). The combination of copanlisib and Tr significantly improved growth inhibition compared to either therapy alone in N87, ESO26 and OE19 cells (p < 0.05).
Copanlisib is an effective monotherapy in some HER2-positive GC cell lines. Combinations of copanlisib and Tr offer greater benefit than either drug alone, and may restore sensitivity to Tr in cells with intrinsic resistance to Tr. The addition of copanlisib to HER2 targeted therapy warrants further investigation in HER2-positive GC.
Clinical trial identification
Legal entity responsible for the study
North East Cancer Research and Education Trust (NECRET).
All authors have declared no conflicts of interest.