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Choose two treatments so that whatever the tumour does to escape the first, it becomes easier to kill with the second. The immune system is a good candidate partner.
An evolutionary double bind pairs therapies with opposing selection pressures. Examples with preclinical support include MAPK inhibition increasing antigen presentation (making escape via MAPK reactivation immune-visible) and antiandrogen resistance via lineage plasticity creating dependence on EZH2. The proposal is to make double-bind logic an explicit design criterion, with a mechanistic screen for pairs in which resistance to A upregulates the target of B.
Shares Too many combinations to test, Acquired resistance to every therapy, RAS / RAF / MEK / ERK (MAPK), Immune checkpoint inhibitors.
Shares Too many combinations to test, Tumour heterogeneity and clonal evolution, Acquired resistance to every therapy.
Shares EZH2, Acquired resistance to every therapy.
Shares Too many combinations to test, Immune checkpoint inhibitors.
Shares Tumour heterogeneity and clonal evolution, Acquired resistance to every therapy.
Shares Tumour heterogeneity and clonal evolution, Acquired resistance to every therapy.
Shares Tumour heterogeneity and clonal evolution, Acquired resistance to every therapy.
Shares BRAF, RAS / RAF / MEK / ERK (MAPK).