Additional file 3: Figure S1. of Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro

Endometrial cancer cell lines in which synergism was observed to the combination of pictilisib (PI3K), apitolisib (PI3K/mTOR), and cobimetinib (MEK) inhibitors. a) Eight cell lines in which synergism was observed to the combination of PI3K and MEK inhibition. b) Eight cell lines in which synergism was observed to the combination of PI3K/mTOR and MEK inhibition. (XLSX 158 kb

Additional file 1: Table S1. of Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro

The 66 primary antibodies used in RPPA in this study are listed. The phosphorylation sites (amino acids) for phospho-specific antibodies are shown. (XLSX 10 kb

BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors

Background: We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors. Methods: The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models. Results: Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively. Conclusion: A clinical trial may be justified to further investigate the utility of IAP inhibitors.</p

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

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 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.</p

Supplementary_material – Supplemental material for Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer

<p>Supplemental material, Supplementary_material for Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer by Naomi Elster, Sinead Toomey, Yue Fan, Mattia Cremona, Clare Morgan, Karolina Weiner Gorzel, Una Bhreathnach, Malgorzata Milewska, Madeline Murphy, Stephen Madden, Jarushka Naidoo, Joanna Fay, Elaine Kay, Aoife Carr, Sean Kennedy, Simon Furney, Janusz Mezynski, Oscar Breathhnach, Patrick Morris, Liam Grogan, Arnold Hill, Susan Kennedy, John Crown, William Gallagher, Bryan Hennessy and Alex Eustace in Therapeutic Advances in Medical Oncology</p