Abstract

The combination of genetic, epigenetic and microenvironment-driven phenotypic heterogeneity within tumours is so great, some argue that resistance to therapy is inevitable and prevention will be the only effective anticancer strategy. For most melanoma, changes in behaviour that reduce sun exposure would reduce its incidence substantially. However, despite raised public awareness of the dangers of excessive sun exposure, the increasing incidence of the disease means that devising an effective antimelanoma therapy remains a priority. Until the identification of activating mutations in BRAF (Davies et al., 2002), an upstream activator of mitogen-activated kinase (MAPK) signalling, as a major driver of melanoma progression in around 50% patients, antimetastatic melanoma strategies were notoriously ineffective. Now, the ability to genotype rapidly those patients with BRAF-mutant melanoma means that inhibitors of activated BRAF such as vemurafenib can be used to deliver ‘personalized targeted therapy’. Consistent with the key role of activated BRAF in melanoma, its inhibition leads to rapid tumour regression and in most cases improved survival. However, despite its initial promise, resistance to anti-BRAF therapy is observed in almost every patient (Sosman et al., 2012). Resistance can be acquired through a wide range of mechanisms including activation of upstream and downstream effectors of MAPK signalling, increased expression of various activated BRAF isoforms and activation of the AKT survival pathway. Thus, currently, there remains no effective cure for metastatic melanoma. As BRAF inhibitors are extremely effective before the emergence of resistance, it is not surprising that considerable effort is being applied to working out how best to use them. Now in two papers, Das Thakur et al. and Beck et al. highlight potential strategies to enhance the effectiveness of vemurafenib. “Discontinuous vemurafenib therapy may forestall the emergence of lethal resistance” Although discontinuous drug administration may yield short-term advantages and prolong survival, it seems likely that other resistance mechanisms will eventually emerge and that remission-free survival will remain elusive. Complementary strategies can be envisaged that either work on BRAF-inhibitor resistant cells via a completely different mechanism or by enhancing cell death by exploiting synergies with BRAF inhibitors. In the report from Beck et al., an examination of the molecular mechanism underlying apoptosis induced by vemurafenib revealed one such potential synergy. While it has been long known that vemurafenib induces apoptosis, mechanistically how this was achieved was not entirely clear. Beck et al. now reveal that vemurafenib induces endoplasmic reticulum (ER) stress in BRAFV600E melanoma cells. Endoplasmic reticulum stress can trigger apoptosis and occurs in response to disruption of normal ER function; nutrient deprivation, calcium imbalance, hypoxia or dysregulated protein glycosylation can lead to accumulation of misfolded proteins and activation of the unfolded protein response (UPR), increased transcription of UPR-associated factors, reduced protein synthesis and ER-associated protein degradation (Hetz, 2012). Together this adaptive response aims to restore normal ER functionality, or if this is not possible, trigger apoptosis. BRAF-mutant melanoma cells treated with BRAF inhibitors increase expression of the pro-apoptotic factor BCL2-interacting mediator of cell death, BIM (Paraiso et al., 2011), which is also elevated in response to ER stress. Beck et al. showed that BIM knockdown reduced vemurafenib-mediated cell death, providing a clue that ER stress could occur on BRAF-inhibition. Consistent with this, they also demonstrated that vemurafenib induces phosphorylation of the translation regulator eIF2a and up-regulated expression of ER-stress-related genes including the transcription factor ATF4, all hallmarks of an ER-stress response. Importantly, knockdown of ATF4 substantially reduced vemurafenib-mediated apoptosis. Significantly, treatment of rapidly proliferating melanoma tumours in a chick embryo model with thapsigargin, a well-characterized activator of ER stress, indicated that activation of ER stress could lead to substantially reduced proliferation and invasiveness. Moreover, although thapsigargin did not increase the effectiveness of BRAF-inhibition in melanoma cells that were highly vemurafenib sensitive, in less sensitive cells, thapsigargin was able to enhance the antitumour effectiveness of the anti-BRAF drug. The authors then went on to ask whether induction of ER stress might be effective in melanoma cells resistant to BRAF inhibitors. Significantly, thapsigargin was able to induce apoptosis in vemurafenib-resistant cell lines in which it inhibited phosphorylation of AKT, but not ERK. Taken together, the data presented by Beck et al. suggest that at least in some circumstances, ER-stress inducers may provide potential therapeutic benefit, especially in melanomas that have acquired BRAF-inhibitor resistance, and also highlight the possible synergy between AKT inhibition and ER-stress induction. The studies from Thakur et al. and Beck et al. suggest that while resistance to BRAF inhibitors is a major barrier to remission-free survival, there are potential strategies that can be adopted that may enhance the efficacy of BRAF-targeted therapies.

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