Oncogenes

High frequency of BRAF mutations in nevi. Pollock, P. M. et al. Nature Genet. 25 Nov 2002 (doi:10.1038/ng1054)

BRAF encodes an oncogenic kinase that is involved in the RAS–RAF–MAPK signalling pathway. Earlier this year, BRAF was found to be mutated in malignant melanoma, but how early in the transformation process does this occur? Pollock et al. now show that mutations in BRAF occur very early in melanoma pathogenesis — at the nevi stage. Some 82% of nevi had an activating mutation in BRAF, resulting in the amino-acid substitution V599E, indicating that this is a crucial step in the initiation of melanoma.

Checkpoints

53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. DiTullio, R. A. et al. Nature Cell Biol. 4, 998–1002 (2002)

53BP1 localizes to double-strand breaks following irradiation, indicating that it might be a checkpoint protein. RNAi of 53BP1 showed that it is required for the ATM-dependent phosphorylation of certain substrates after DNA damage, and for the G2–M checkpoint. Interestingly, in several cancer cell lines that have mutant TP53, 53BP1 foci form even in the absence of irradiation, which has led the authors to suggest that an activated checkpoint pathway might provide a selective pressure for mutation of TP53.

Tumorigenesis

Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Roberts, C. W. M. et al. Cancer Cell 2, 415–425 (2002)

The SWI/SNF chromatin remodelling complex might act as a tumour suppressor, but definitive evidence has been lacking. Now, a reversible inactivating conditional allele of Snf5 — a core subunit of SWI/SNF — has been generated to investigate this. Inactivation of Snf5 results in the formation of tumours — T-cell lymphomas and rare rhaboid tumours — in 100% of mice with an average latency of 11 weeks, confirming that it does act as a tumour suppressor.

Therapeutics

Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents. Zhu, J. et al. J. Natl Cancer Inst. 94, 1745–1757 (2002)

COX2 inhibitors act as chemopreventive drugs by sensitizing cancer cells to apoptosis, but why do agents that inhibit COX2 to a similar extent show different potencies against cancer cells? A systematic chemical approach to modify the structures of celecoxib and rofecoxib was used to generate compounds that could be tested for their ability to induce apoptosis of prostate cancer cells. The structural requirements for COX2 inhibition are different from those for apoptotic induction — which occurs by downregulating AKT and ERK2 — so existing COX2 inhibitors could be modified to maximize their ability to kill cancer cells.