Importantly, FGTI-2734 inhibited the growth of xenografts derived from four patients with pancreatic cancer with mutant KRAS (2 G12D and 2 G12V) tumors.
Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746-T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V).
In conclusion, whilst oncogenic KRAS mutation might activate Yap in other cell types, we could find no evidence for this in myoblasts because the expression of KRAS G12V expression did not change Yap/Taz activity in myoblasts and there was a limited overlap in gene expression between KRAS G12V and YAP1 S127A-driven tumours.
In combination with p53 silencing, KRAS(G12V) alone was sufficient to fully transform the immortalized HPDECs, and MYC markedly accelerated the development of tumors.
The introduction in different orders of the oncogenic allele of Ras (H-Ras(G12V)) and the mutant p53(DD) that disrupts the p53 pathway yielded tumors displaying major differences in histological features, tumorigenicity, and metastatic behavior.
In contrast, the combination of p53 RNAi knockdown with expression of oncogenic H-Ras(G12V) transformed the p16-deficient BAR-T cells, as evidenced by their loss of contact inhibition, by their formation of colonies in soft agar, and by their generation of tumors in immunodeficient mice.