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

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.

Overcoming Resistance to HER2-Directed Therapies in Breast Cancer

“…Further research is needed to determine if other inhibitor combinations are safe and can improve patient outcomes. Finally, PTEN mutations promote MAPK pathway dependency in breast cancer [ 78 ]; the combination of PI3K and MEK inhibitors have been shown to improve responses to HER2+ gastric cancer [ 79 ], and future research is needed to determine if this combination could improve outcomes in patients with HER2+ breast cancer.…”

Integrated analysis of pivotal biomarker of LSM1, immune cell infiltration and therapeutic drugs in breast cancer

“…A positive effect on metastatic spread can be achieved with sorafenib monotherapy and combination therapy. When used in combination, refametinib and sorafenib act synergistically in multiple models to reduce tumour growth and prolong survival 28–31 . In addition, trametinib has been reported to inhibit the growth of ERRα and KRAS‐mutant lung cancer in different cancers 32,33 .…”

“…When used in combination, refametinib and sorafenib act synergistically in multiple models to reduce tumour growth and prolong survival. [28][29][30][31] In addition, trametinib has been reported to inhibit the growth of ERRα and KRAS-mutant lung cancer in different cancers. 32,33 Although reduced TNFα production was observed in vivo, the combination therapy activated CD8+ T cell-mediated immunity and increased survival in an immunoreactive mouse model carrying glioma.…”

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

“…63 In addition, some studies have shown that inhibition of PI3K or MEK alone, or in combination with anti-HER-2 therapy, might be a reformative treatment scheme for some patients with HER-2 positive GC. 64 Approximately 34-59% of the patients with HER-2 positive GC also overexpress HER-3 and are resistant to trastuzumab, 65 which can be attributed to the negative feedback regulation of HER-3 mediated by the HER-2-dependent P13K-AKT pathway, making trastuzumab unresponsive to ligand-dependent dimerization of HER-2/HER-3. 66…”