Getting at MYC through RAS.

The discovery of oncogenes provided insight into the molecular underpinnings of cancer and suggested the promise of novel molecular strategies for cancer treatment as highlighted in this issue by Yaari et al. and by Bishop previously (1, 2). However, only recently have effective drugs that target oncogenes been successfully introduced into the clinical setting. The flagship example of a targeted therapeutic is Gleevec (imatinib), which targets the BCR-ABL, c-Kit, and the plateletderived growth factor receptor oncoproteins as well as other tyrosine kinases. Gleevec has been proven effective in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor (3, 4). Why has it been so difficult to discover drugs that target oncogenes to treat cancer? Does the discovery of Gleevec suggest that we are on the verge of developing many new drugs for the treatment of cancer? The difficulty in identifying drugs that target oncogenes for the treatment of cancer is multifactorial. On a theoretical level, most cancers are likely the consequences of many genetic lesions, so the repair or inactivation of one associated mutant gene product may not sufficiently affect the pathobiology of a cancer to have clinical utility. For most tumors, the best oncogenes to target have yet to be identified. Even if a targeted therapy succeeds in having a clinical effect, tumors are genomically unstable and may easily acquire compensatory genetic lesions. Even if certain oncogenes are good targets, it is not clear how they would be identified. Even if they are good targets, many oncogenes are not readily ‘‘drugable’’ using small molecules. Even if drugable, many oncogenes serve essential cellular functions, and sufficiently targeting a mutant oncogene may also inactivate the normal proto-oncogene, thereby causing high toxicity. Regardless of the various theoretical and practical limitations to targeting oncogenes for the treatment of cancer, the discovery of Gleevec provides a proof of the principle that rational molecular therapeutics can work. Moreover, experimental evidence from many groups shows in transgenic mouse models that oncogene-induced cancers may generally be reversible on oncogene inactivation (5–8). Although cancers in mouse models may be less genomically complex than their human equivalents, these studies illustrate that under some circumstances, cancer is reversible. Thus, the challenge is to understand these circumstances and then identify drugs that can safely and effectively be used to inactivate oncogenes for the treatment of cancer. In this issue of Clinical Cancer Research , Yaari et al. have shown an important principle in the development of therapies for the treatment of cancer. Rather than directly target an oncogene of interest, disrupting an essential upstream regulator may more effectively inhibit the oncogene signaling pathways to reverse cancer. These results illustrate how an understanding of the molecular pathways that regulate activation of an oncogene may be used to identify a potential molecular target.