Mechanisms of Disease: Oncogene Addiction-A Rationale for Molecular Targeting in Cancer Therapy

I Bernard Weinstein; Andrew K Joe

Disclosures

Nat Clin Pract Oncol. 2006;3(8):448-457. 

In This Article

Evidence for the Concept of Oncogene Addiction

Evidence that supports the concept of oncogene addiction has been obtained in three diverse systems: genetically engineered mouse models of human cancer ( Table 1 ), mechanistic studies in human cancer cell lines ( Table 2 ), and clinical trials involving specific molecular targeted agents ( Table 3 ). Several investigators have generated transgenic mice that overexpress an oncogene in a specific target tissue under conditions in which the oncogene can be switched on or off ( Table 1 ). Felsher and Bishop[6] used this model system and found that switching on the c-myc oncogene in the hematopoietic cells of mice led to the development of T-cell and myeloid leukemias; however, when this gene was subsequently switched off the leukemia cells stopped dividing and displayed differentiation and apoptosis. Dependence on continued expression of a single oncogene for maintenance of the neoplastic state has also been seen in similar murine models of other tissues ( Table 1 ), including: myelocytic leukemia induced by the Bcr-Abl oncogene;[7] melanoma induced by the H-ras oncogene;[8] lung tumors induced by the K-ras oncogene;[9] pancreatic β-cell tumors and osteogenic sarcoma induced by the c-myc oncogene;[10,11] breast (mammary) tumors induced by the Her-2/neu oncogene;[12,13] breast tumors induced by the c-myc oncogene;[14] and breast tumors induced by the Wnt oncogene.[15] It is of interest that in the c-myc breast cancer model, when the c-myc oncogene was switched off, although 50% of the breast tumors regressed, the remaining 50% showed only partial regression. Furthermore, breast tumors that recurred were found to be c-myc independent and some of these displayed an activated K-ras oncogene.[14] Similarly, in the Her-2/neu breast tumor model[12] ( Table 1 ) tumors that recurred were found to be Her-2/neu independent, and this was recently found to be caused by increased expression of the transcription factor Snail.[13] In the Wnt-1 murine model ( Table 1 ), even though downregulation of Wnt-1 resulted in rapid and extensive regression of aneuploid and invasive breast tumors and pulmonary metastases, a number of breast tumors recurred that were Wnt-independent. Apparently, recurrence was caused by acquisition of mutations in the p53 tumor suppressor gene.[15] The relevance of these examples of 'escape from oncogene addiction' will be discussed later with respect to the themes of oncogene addiction in human cancers and combination therapy.

A variety of studies using human cancer cell lines also indicate that although these cells are aneuploid and carry numerous genetic and epigenetic abnormalities, they can also be highly dependent on the activity of a single oncogene for maintaining the malignant phenotype ( Table 2 ). Blocking expression of the oncogenes for HER2, cyclin D1, K-ras, β-catenin, cyclin E, B-Raf, or microphthalmia transcription factor (MITF) using either antisense DNA or RNA interference (RNAi) strategies can markedly inhibit the in vitro growth of various types of human cancer cells.[16,17,18,19,20,21,22,23,24,25,26,27] In some cases blocking oncogene expression also increases the sensitivity of these cells to specific chemotherapy agents and inhibits their tumorigenicity in mice.[19] As a result of the efficacy of the RNAi method for inhibiting the expression of specific genes, the list of such examples of oncogene addiction is now rapidly expanding.

The most convincing and clinically relevant evidence for the concept of oncogene addiction comes from the increasing number of examples (i.e. prospective randomized trials) of the therapeutic efficacy of antibodies or drugs that target specific oncogenes in human cancers ( Table 3 ). One of the earliest examples is the use of the antibody trastuzumab,[28] which targets the receptor tyrosine kinase HER2. This membrane associated receptor is overexpressed in 20-30% of breast cancers and it is now established that use of trastuzumab in these patients can markedly inhibit tumor growth and prolong patient survival in both the adjuvant and metastatic settings.[28,29] We should, however, emphasize that the therapeutic effects of trastuzumab may be mediated at least in part via immune mechanisms.[30] Within the past few years several low molecular weight drugs have been developed that target and inhibit the activity of other specific protein kinases that have key roles in the growth and survival of human leukemia and carcinoma cells.[31,32] The remarkable therapeutic efficacy of some of these compounds ( Table 3 ) provides direct evidence for the concept of oncogene addiction. Examples include imatinib, which targets the oncogenic BCR/ABL protein in chronic myeloid leukemia,[31] and also targets the product of the oncogene c-kit in gastrointestinal stromal tumors,[33] and the EGFR-targeted drugs gefitinib and erlotinib in non-small-cell lung carcinoma (NSCLC), pancreatic cancer, and glioblastoma.[32,34,35,36,37,38] Recent studies suggest that cetuximab, a monoclonal antibody that targets the EGFR, could have significant antitumor activity in head and neck and colorectal carcinomas;[39,40] and that bevacizumab, a monoclonal antibody to VEGF, might have significant antitumor activity in carcinomas of the breast, colon and kidney.[41,42,43] These clinical studies also provide insights into the phenomenon of oncogene addiction. For example, in a subset of patients with chronic myeloid leukemia who initially responded to imatinib but later suffered a relapse, examination of the leukemic cells showed a de novo mutation in the kinase domain of the BCR/ABL protein, which blocked the inhibitory activity of imatinib.[44] Likewise, it was recently found that the tumor from a patient with NSCLC, who relapsed 2 years after an initial dramatic response to gefitinib, had acquired a second point mutation in the kinase domain of the EGFR, which blocked the binding of gefitinib.[45] The strong selective pressure for emergence of cells that carry de novo mutations in the respective oncogenes indicates the remarkable dependence of these neoplastic cells on these oncogenes, and provides further evidence for the concept of oncogene addiction. At the same time these findings reveal the emergence of resistance mechanisms to molecular targeting agents. Studies in progress indicate that, in the case of the Bcr/Abl oncogene, there are other drugs that can inhibit the kinase activity of the mutant BCR/ABL protein,[46] and it could be possible to develop similar drugs that act on resistant mutants of the EGFR and resistant forms of other protein kinases. Furthermore, it might be possible to suppress the emergence of these types of resistant cells by combining a specific protein kinase inhibitor with an agent that inhibits cell proliferation via a different mechanism; this approach would limit the likelihood of the emergence of mutant clones. This aspect is further discussed later in this review in the section on combination therapy.

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