Oncogenes come of age

Abstract

Mutations of proto-oncogenes are common events in the pathogenesis of cancers, as shown in a wide range of studies during the 30 years since the discovery of these genes. The benefits of novel therapies that target the products of mutant alleles in human cancers, and the demonstrated dependence of cancers in mouse models on continued expression of initiating oncogenes, are especially promising signs that revolutionary improvements in cancer care are possible. Full realization of the promise of targeted therapies, however, will require better definitions of the genotypes of human cancers, new approaches to interrupt the biochemical consequences of oncogenic mutations, and a greater understanding of drug resistance and tumor progression. In this paper, we summarize recent efforts toward these goals in our laboratory and others.

Figure 1

Oncogenic K-ras is required for lung tumor maintenance with or without loss of tumor suppressor genes. Samples of lung tissue, stained with hematoxylin and eosin, after exposure to doxycycline for 1 or 2 months and after withdrawal for 7 days are shown (Fisher et al. 2001). Withdrawal of doxycycline leads to rapid tumor regression in bi-transgenic CCSP-rtTA/TetOKras^G12D in a wild-type (WT) background (A) and in an Ink4A/Arf-deficient background (B). Similar results were obtained in a p53-deficient background (Fisher et al. 2001). Magnification, 100x.

Figure 2

Lung tumors with EGFR mutations respond dramatically to treatment with tyrosine kinase inhibitors. Chest radiographs (A) and chest computerized tomography-generated images (B) showing a tumor response to gefitinib (A) after 4 days of treatment and erlotinib (B) after 4 months of treatment in two patients, one of which is known to have a tumor with an EGFR mutation. (C) Magnetic resonance images of lungs from a mouse expressing the EGFR L858R mutant before (left panel) and after 4 days (right panel) of erlotinib treatment.

Figure 3

Pie chart depicting the frequency of known proto-oncogenes found to be mutated in non-small-cell lung cancers. As discussed in the text, these genes all encode components of the EGFR signaling network.