Multi-Targeted Disruption of Inter-Clonal Cooperative Interactions Using Existing Drugs to Decrease the Metastatic Potential of Tumours

Despite great therapeutic advances, cancer remains one of the leading causes of death worldwide. Although metastasis is responsible for most cancer-related deaths, standard anti-cancer therapies are mainly designed to control tumour growth by affecting cell proliferation and viability. The main challenge in targeting metastasis arises from our limited understanding of this dynamic and complex process. For instance, increasing evidence indicates that many metastatic steps often involve cooperation between different clones to collectively migrate, invade, disseminate and colonize distant tissues. Although such cooperative interactions can promote tumour aggressiveness, they can also reveal dependencies between clones, potentially exposing vulnerabilities that can be therapeutically exploited. We have previously used an in vitro breast cancer model consisting of a weakly metastatic cell line (MCF7) and a highly metastatic line (MDA-MB-231) to investigate potential inter-clonal cooperative interactions during migration and invasion. Here, we have developed a proof-of-principle approach aimed at decreasing the overall metastatic potential of tumours via disrupting inter-clonal cooperative interactions at multiple levels and affecting multiple pathways. We used Erlotinib and either FAK, MEK, MET or RET approved inhibitors to identify additive or synergistic effects on the migration of both clones, alone or in co-culture. We also employed transcriptomics to identify additional targets that could be used in combination with Erlotinib. These approaches aimed to synergistically target multiple nodes and levels within the cooperative signalling network. The study provides a framework for developing more effective anti-metastatic therapies that account for tumour heterogeneity and exploit the therapeutically targetable dependencies that promote cooperative metastatic behaviors.