Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage

Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage

Blog Article

Abstract Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown.Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells 910-005270 and derive multiple stable clones with various degrees of aneuploidy.We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics.

Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens.Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction.Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF gator phi gator inhibition.

Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors.We validate these results in human cancer cell lines.Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors.

Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells.