Background: Targeted therapies have gained significant traction as a preferred treatment option for cancer due to their increased selectivity. By targeting well profiled cancer biomarkers and amplified signaling pathway constituents, these therapies effectively inhibit characteristic unregulated cell growth and survival. However, efficacy is often reduced as a result of compensatory signaling by the cancer cells, conferring therapeutic resistance. As such, combining therapeutics has been shown to prevent this response and re-sensitize cells to treatment.
In gastroesophageal cancer, the PI3K/AKT and MAPK pathways are regularly mutated or amplified, and there is evidence of compensatory crosstalk between them. As such, it is proposed that dual blockade of these pathways would be an effective treatment strategy. Alpelisib is an FDA approved PI3K inhibitor used in the treatment of advanced breast cancer, following the success of the SOLAR-I clinical trial, and gefitinib is an FDA approved EGFR inhibitor used in the treatment of non-small cell lung cancer. The combination of these two drugs, already approved as monotherapies, may present a promising new therapeutic strategy.
Aim: To determine the efficacy of combination therapy involving the PI3K inhibitor alpelisib and the EGFR inhibitor gefitinib in a metastatic gastroesophageal cancer model under different culture conditions.
Methods: The responsiveness of the circulating tumour cell line UWG02CTC, derived from a patient with metastatic gastroesophageal carcinoma, to alpelisib, gefitinib, and combination was assessed under both two dimensional (where they grow as a mixed adherent and loose aggregate culture) and ultra-low attachment (ULA, where they are forced into a non-adherent loose spheroid culture) conditions. Synergistic relationships were analysed using ClacuSyn software.
Results: UWG02CTCs were sensitive to both alpelisib and gefitinib as single agents, with IC50s of 7 ± 2.3 uM (mean ± SD, n=7), and 273 ± 66.8 nM (n=6), respectively. Fixed-ratio assays determined the combination of both drugs to be synergistic in both 2D and ULA conditions (combination index CI < 1). Dose-reduction indices (DRIs) for alpelisib and gefitinib, respectively, were 4-fold and 2-fold higher in ULA compared to 2D, suggesting increased sensitivity under ULA conditions.
Conclusions: Preliminary work suggests that the combination of alpelisib and gefitinib may be an effective therapeutic strategy to combat GOC metastatic disease. Validation of this combined therapy in in vivo experimental models would provide the grounds for escalation into phase I clinical trials, and the potential for the development of a promising new intervention.