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Inhibition of melanoma development in the N ras (Q61K) :: I nk4a −/− mouse model by the small molecule BI ‐69A11
Author(s) -
Feng Yongmei,
Lau Eric,
Scortegagna Marzia,
Ruller Chelsea,
De Surya K.,
Barile Elisa,
Krajewski Stan,
AzaBlanc Pedro,
Williams Roy,
Pinkerton Anthony B.,
Jackson Michael,
Chin Lynda,
Pellecchia Maurizio,
Bosenberg Marcus,
Ronai Ze'ev A.
Publication year - 2013
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12033
Subject(s) - neuroblastoma ras viral oncogene homolog , melanoma , cancer research , gene expression , mutant , microbiology and biotechnology , downregulation and upregulation , gene , biology , cell culture , cell growth , mutation , immunology , kras , chemistry , genetics
Summary 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.