Year: 2012
Type: article
Abstract: In the not so distant past, clinical management of melanoma beyond surgical excision was largely futile. As with many other diseases in medical oncology, the treatment for metastatic melanoma was centered upon chemotherapies or immunologic modulations with little to recommend them in terms of objective response rates, and substantial toxicity. When rare responses were seen, we had little insight as to why a given patient would respond whereas another would not. Much has changed in the last 5–10 years. Melanoma genomes have been sequenced, novel oncogenes driving the disease discovered, and highly effective therapies have been approved (Chapman et al., 2011). In many ways the field has moved so far forward in so little time that fundamental questions about how melanoma cells actually respond to these new therapies risk being couched in favor of new drug combination regimens and ever more complex mechanisms of acquired RAF inhibitor resistance. About half of melanomas harbor activating mutations in the BRAF gene, rendering its protein kinase product constitutively active. These mutations appear to be an early event in the disease, as they are present in most nevi. Potent inhibitors of the RAF kinases have proven to be effective treatment for many, but not all patients harboring activating mutations in BRAF (Chapman et al., 2011). Numerous groups have investigated acquired resistance to such agents (reviewed in Mcmahon, 2011), and because response is often short-lived, the identification of acquired resistance pathways is a high priority. Relatively less attention has been paid to why patients that harbor identical drug-sensitizing mutations in BRAF will have markedly different responses to the identical targeted therapy. Why do only about half of such patients enjoy substantial shrinkage of their disease? Can primary (de novo) RAF inhibitor resistance mechanisms be understood in molecular terms and therefore predicted before treatment is administered? If so, could RAF inhibitor therapy be either modified to maximize response or held in favor of other therapies, specifically in those patients predicted to be resistant, with the goal of effectively treating the greatest proportion of patients from the onset? Work from Biechele et al. (2012) has shed new light on the issue of primary responses to Raf inhibition in BRAF mutant melanoma cells and implicates a Raf inhibitor-induced modulation of the Wnt pathway as a primary determinant of response to RAF inhibition. Cross talk between signaling pathways is a common occurrence in cancer cells, undoubtedly more common than we currently appreciate because of the inherent difficulty in examining parallel pathways in an unbiased manner after experimental manipulation of a system. Cancer pathways are mutated or otherwise deregulated because they are important for growth. Cells are dynamic systems, so it is not surprising to learn that inhibiting the RAF/MEK/ERK pathway at the level of RAF in BRAFV600E expressing melanoma cells leads to alteration in the Wnt/beta catenin pathway, because we know from prior work that Wnt signaling is important in the genesis and maintenance of melanoma (Delmas et al., 2007). What is surprising is the directionality of change and how it occurs (Figure 1). Crosstalk between the Wnt and Raf pathways in melanoma. Biechele et al. (2012) use siRNA screening to identify kinases whose depletion might alter Wnt signaling using a beta catenin reporter-modified BRAFV600E A375 human melanoma cell line. Surprisingly, siRNAs against BRAF and MAPK1 activated this reporter, indicating that the constitutively active RAF pathway in these cells tonically inhibited the Wnt pathway at baseline. Drugs on the RAF/MEK/ERK pathway (both Raf and MEK inhibitors) activated the reporter as well, in a dose-dependent manner. As a result of these observations and prior work in their laboratory, they concluded that activation of Wnt signaling, at the level of beta catenin, was a key event in acute responses to inhibition of the Raf/MAPK pathway. The authors demonstrate that WNT3A and PLX4720 synergize in A375 cell killing though an apoptosis mechanism, and that this effect depends on beta catenin, consistent with their reporter screens. Interestingly, the authors find that some melanoma cell lines responded to RAF inhibition by decreasing levels of AXIN1 protein, a key negative regulator of Wnt signaling, and that the lines demonstrating this response were those that would undergo apoptosis in response to PLX4720. These results together suggest a potentially important distinction between melanomas harboring otherwise identical mutations in BRAF. Specifically, the work implies that if a given melanoma activates Wnt signaling (likely by inhibiting levels of AXIN) in response to RAF inhibition, it will be sensitive, whereas those melanomas that fail to do so will be resistant to RAF inhibition from the start of therapy. These findings suggest a somewhat paradoxical approach to cancer treatment: that we should stimulate one oncogenic pathway (Wnt) while inhibiting another (RAF/MEK/EFRK) to optimize therapy. Intentionally activating Wnt signaling with therapeutic intent in melanoma would raise controversy, because the Wnt pathway is largely thought to be oncogenic in its own right in this disease. While this approach requires further examination in a wider array of preclinical melanoma models, the work underscores the importance of understanding primary cellular responses to pathway inhibition. The work further underscores the importance of obtaining ‘on treatment’ biopsies per protocol in ongoing trials with agents in melanoma, because understanding how a cancer will respond to a therapy requires knowing the earliest changes in the tumor cell induced by the drug in question. It is only through such an understanding will we be able to further personalize the application of specific therapies beyond genotyping of BRAF.
Source: Pigment Cell & Melanoma Research
Author: Eric A. Collisson
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2314735100