Joining the scores of scientists who are moving to what will hopefully be a much better, safer space (and is not controlled by an evil man). See you on the other side!

15/ Altogether, we propose that aneuploid cells increase CRAF/MEK/ERK pathway activity, which helps them overcome the elevated DNA damage. Inhibition of CRAF/MEK/ERK signaling could therefore sensitize aneuploid cells to DNA damage inducers.

14/ Finally, we analyzed data from pancreatic PDXs and breast cancer patients treated with olaparib and immunotherapy. Resistance was associated with high RAF/MEK/ERK pathway activity, especially in highly aneuploid tumors.

13/ We found that MEK overexpression reduced sensitivity to etoposide and olaparib. Moreover, trametinib sensitized highly aneuploid clones to etoposide, suggesting the potential benefits of combining MEK/ERK inhibitors with DDR inhibitors.

12/ As a result, these clones were more sensitive to MEK inhibitors (trametinib, selumetinib) and the ERK inhibitor ulixertinib, demonstrating dependency on the RAF/MEK/ERK pathway.

11/ CRAF downstream targets MEK and ERK also showed significantly higher activity in aneuploid clones, indicating elevated RAF/MEK/ERK signaling.

10/ Inhibiting CRAF with TAK632 sensitized highly aneuploid clones to DNA-damaging agents like etoposide and olaparib, confirming that CRAF activation helps aneuploid cells overcome DNA damage.

9/ Importantly CRAF activity is linked to the DNA damage response (DDR) and is activated in response to DNA damage. We found that etoposide increased CRAF activity in parental RPE1 cells, and higher CRAF activation correlated with resistance to DNA-damaging drugs in cancer cells.

8/ Additionally, highly aneuploid tumors in pediatric PDX models were more sensitive to RAF inhibitors. Thus, aneuploid cancer cells also activate CRAF.

7/ We investigated whether CRAF activity is linked to high aneuploidy in human cancer cells. Analysis of hundreds of cancer cell lines showed increased CRAF activity in highly aneuploid cells.