Many targeted cancer therapies work by inhibiting oncogenic signalling, but unfortunately their initial control of tumour growth is often followed by subsequent resistance, calling for alternative strategies. Increasing evidence suggests that there is an ideal level of oncogenic signalling conducive to tumour initiation and maintenance, and that deviations from this level might represent a vulnerability. Therefore, the group of René Bernards reasoned that intentional further activation of oncogenic signalling, rather than its inhibition, could represent an alternative strategy leading to cancer cell death.

Given the increased reliance on stress response pathways in the context of LB-100 inhibition, the authors surmised that targeting the stress response pathways might be synthetic lethal with hyperactivation of oncogenic signalling in causing cancer cell death. To explore this idea, the authors carried out custom, stress-focused drug screens on two CRC cell lines and identified inhibitors of the cell cycle regulators WEE1 and CHK1 as sensitizing to LB-100 treatment. Furthermore, genome-wide CRISPR knockout screens identified synthetic lethality between WEE1 loss and LB-100 in one of the CRC cell lines.