Researchers at Rockefeller University report that a new single-cell screening platform, PerturbFate, can trace how many different genetic disruptions converge on common regulatory programs that drive resistance to the melanoma drug vemurafenib, pointing to potential combination-therapy targets.
A study in Nature describes PerturbFate, a CRISPR-interference screening approach designed to follow how gene perturbations reshape cell states using multimodal single-cell readouts.
In the paper, the researchers report that PerturbFate can profile chromatin accessibility alongside RNA measurements—capturing both newly synthesized (nascent) and pre-existing RNA—while also identifying which guide RNA perturbed each cell.
As a proof of concept, the team applied the method to A375 melanoma cells carrying the BRAF(V600E) mutation, a widely used model for studying resistance to vemurafenib, a BRAF inhibitor used in melanoma treatment. Based on prior resistance screens and expression profiles, they selected 143 candidate genes linked to vemurafenib resistance and analyzed data from more than 300,000 cells.
The Nature study reports that many distinct perturbations pushed cells toward a shared, drug-resistant state. By reconstructing gene regulatory networks, the authors identified convergent regulatory programs—including roles for MAPK and Hippo/YAP signaling—and report that co-targeting key downstream programs improved sensitivity to vemurafenib in their experimental system.
Rockefeller University said the group has made the experimental and computational tools underlying PerturbFate openly available, and plans to extend the approach beyond cultured cells into living models to study other complex disease settings, including aging and Alzheimer’s disease.
