Inhibition of melanoma development in the N ras (Q61K) :: I nk4a −/− mouse model by the small molecule BI ‐69A11

• Published in: Pigment cell and melanoma research 2013-01, Vol.26 (1), p.136-142
• Main Authors: Feng, Yongmei, Lau, Eric, Scortegagna, Marzia, Ruller, Chelsea, De, Surya K., Barile, Elisa, Krajewski, Stan, Aza‐Blanc, Pedro, Williams, Roy, Pinkerton, Anthony B., Jackson, Michael, Chin, Lynda, Pellecchia, Maurizio, Bosenberg, Marcus, Ronai, Ze'ev A.
• Format: Article
• Language: English
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12033

To date, there are no effective therapies for tumors bearing NRAS mutations, which are present in 15–20% of human melanomas. Here we extend our earlier studies where we demonstrated that the small molecule BI ‐69 A 11 inhibits the growth of melanoma cell lines. Gene expression analysis revealed the induction of interferon‐ and cell death‐related genes that were associated with responsiveness of melanoma cell lines to BI ‐69 A 11. Strikingly, the administration of BI ‐69 A 11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated N ras and a deletion of the I nk4a gene ( N ras (Q61K) :: I nk4a −/− ). Biweekly administration of BI ‐69 A 11 starting at 10 weeks or as late as 24 weeks after the induction of mutant N ras expression inhibited melanoma development (100 and 36%, respectively). BI ‐69 A 11 treatment did not inhibit the development of histiocytic sarcomas, which constitute about 50% of the tumors in this model. BI ‐69 A 11‐resistant N ras (Q61K) :: I nk4a −/− tumors exhibited increased CD 45 expression, reflective of immune cell infiltration and upregulation of gene networks associated with the cytoskeleton, DNA damage response, and small molecule transport. The ability to attenuate the development of NRAS mutant melanomas supports further development of BI ‐69 A 11 for clinical assessment.