opinion piece in @trendscancer with @IcrLordLab and @ilirjanabajrami on "Synthetic Lethality and Cancer – Penetrance as the Major Barrier" authors.elsevier.com/a/1XqSw8Z12yBz…
TLDR version: despite a decade+ of screens for synthetic lethals, relatively few robust hits have been identified 1/n
TLDR version: despite a decade+ of screens for synthetic lethals, relatively few robust hits have been identified 1/n
Many/most hits only identified in a single screen. A lot of this has been attributed to limitations of RNAi screens (high false positive and false negative rates), so there is much anticipation that CRISPR screens will solve the problem (due to reduced false pos/neg rates). 2/n
We argue that a major reason for the lack of reproducible hits is that many synthetic lethal interactions are highly context specific - i.e. A and B are only synthetic lethal in a specific tissue type or, more worryingly, in a specific genetic background. 3/6
This observation is consistent with the results of recent screens for pairwise genetic interactions in cancer cell lines, where many hits are apparently cell line specific, and with some results from model organisms, where trigenic interactions have been studied. 4/6
Given the heterogeneity of cancer cells this is very problematic. We want to identify synthetic lethals that are highly penetrant, i.e. most tumour cells with a particular mutation will respond to drugs targeting a synthetic lethal partner, otherwise hard to see clinical use. 5/6
Rest of paper discusses some approaches (wet & dry) that might help prioritise screen hits that are more likely to be highly penetrant. This is more speculative. I'd be happy if ppl took on board the message that the lack of robust hits may be due to genetics, not just RNAi. 6/6
