June 2015, Vol 4, No 3
BRAF Mutations: An Old Oncogene and a New Target in Non–Small Cell Lung CancerUncategorized
Lung carcinoma has been the leading cause of cancer deaths in the United States and worldwide despite advances in chemotherapy.1,2 Management of non–small cell lung cancer (NSCLC) has evolved significantly since 2004, when mutations in epidermal growth factor receptor (EGFR) were found to be the determining factor of response to gefitinib in a small subset of patients.3,4 This has led to the discovery of an increasing number of driver mutations over the past decade, allowing advancement in targeted and personalized therapy. For example, mutations in several other genes, including KRAS, ALK, HER2, BRAF, ROS1, PI3KCA, RET, and MET, were also found to be involved in carcinogenesis of NSCLC. Currently, only about a third of all NSCLCs are left without a known driver mutation.5 However, therapeutic approaches are still limited because of the lack of validated targeted therapies available for most of the abovementioned mutations.
The MAPK/ERK pathway is one of the most crucial pathways that cells utilize for growth and survival. During normal MAPK/ERK signaling, the appropriate ligand arrives and binds to a tyrosine kinase receptor such as MET, EGFR, or HER2 located on the cell membrane. The activated receptors can phosphorylate the downstream target RAS, which upon activation can recruit RAF kinase to the cellular membrane to be further phosphorylated.6 Three RAF isoforms exist (ARAF, BRAF, and CRAF [Raf-1]), belonging to the family of serine/threonine protein kinases. Among the 3 RAF kinases, BRAF is the major signal transducer in the activation of MEK and ERK, as it displays the highest affinity for MEK1/2 (Figure).7 Activated BRAF phosphorylates downstream MEK, which in turn phosphorylates ERK, which can translocate into the nucleus and phosphorylate appropriate transcription factors responsible for cellular proliferation, differentiation, senescence, and apoptosis. Therefore, components of the MAPK/ERK pathway have been the targets of interest for cancer therapeutics.
A number of activating somatic BRAF mutations were first identified in various cancers in 2002, occurring in approximately 8% of all cancers and 3% of lung cancers.8,9 More than 50 missense mutations in the BRAF gene have been identified thus far, with the majority of them mapped to the kinase domain. Biochemical analysis of cells transfected with activating BRAF mutations shows an elevated level of phosphorylated ERK1/2.9 Mutations found outside the kinase domain can also increase BRAF activity by altering phosphorylation sites (S364, S428, and T439) on BRAF that are required for AKT-mediated inactivation.8-10 Improper inactivation leads to prolonged BRAF activation and thus can stimulate cell proliferation and transformation in the absence of RAS activation.
BRAF Mutations in Lung Cancer
BRAF mutations have been identified in a variety of cancers, including approximately 50% of malignant melanoma and papillary thyroid cancer, and to a much lesser degree (<30%) in ovarian serous adenocarcinoma and colorectal cancer, and rarely (<5%) in non-Hodgkin lymphoma and NSCLC.11 The most common BRAF mutation is an amino acid substitution of valine to glutamate at residue 600 (V600E) in the activation segment of the kinase domain, causing BRAF to be constitutively active. V600E mutations account for almost all (>90%) of BRAF mutations in melanoma but only about half in NSCLC. Furthermore, BRAF mutations in NSCLC are much more diverse and show a wide spectrum of kinase activity compared with those found in melanoma.12
The role of BRAF in carcinogenesis has been demonstrated in vivo, where transgenic expression of BRAF V600E within lung tissues of mice results in the development of lung cancers with bronchioalveolar carcinoma features similar to those observed in humans.13 Consistent with the notion that continued BRAF activation is required for maintenance of the tumor, removal of the mutant transgene leads to dramatic tumor regression, as well as marked dephosphorylation of MEK1/2 and ERK1/2 and a decrease in cyclin D level.13 Importantly, in vivo pharmacologic inhibition of MAPK/ERK with a specific MEK inhibitor leads to tumor regression and increased apoptosis.13 Together, these findings support BRAF V600E as an oncogenic mutation and demonstrate the dependency of BRAF-mutant lung tumors on sustained activation of MAPK signaling.
The majority of BRAF mutations occur within exon 11 or 15. Some of the most common BRAF mutations are V600E and D594G (exon 15), and G469A (exon 11). Among the reported series, only 2 groups, Paik et al14 and Kinno et al,15 found a substantially higher percentage of the G469A mutation in NSCLC patients. According to Paik et al,14 the G469A mutation may be related to a history of tobacco use. However, all patients included in their study were either current or former smokers.14 In fact, Kinno et al15 reported no such association in their study, in which only half of the patients with BRAF-mutated tumors had a history of smoking.
Molecular profiling studies have shown that activating mutations in BRAF, EGFR, HER2, and KRAS genes are generally nonoverlapping in NSCLC.16 However, in the case series reported, several rare cases of concomitant mutations have been described. Marchetti et al17 reported 2 tumors harboring concomitant BRAF V600E and EGFR mutations, and Kinno et al15 reported 5 tumors with concomitant non-V600E BRAF and EGFR mutations. In addition, Cardarella et al18 found 1 patient with a BRAF V600E mutation and concurrent PIK3CA mutation and 2 patients harboring activating G646 mutations and KRAS mutations concomitantly. Another 2 case series also found concomitant KRAS with BRAF mutation.15,19 The question of whether coexisting driver mutations exert the same oncogenicity remains unresolved, and it poses an extreme challenge in the selection of a treatment option that best suits the patient. In addition, coexistence of 2 mutations can result in the emergence of resistance clinically. For example, in the presence of oncogenic RAS, inhibition of BRAF V600E mutation increases dimerization between BRAF (non-V600E or wild-type [WT]) and CRAF, leading to further activation of MAPK/ERK signaling.20,21 Therefore, extended genotyping may be necessary prior to initiating selected targeted therapy.
Several authors have reported the incidence of BRAF mutation in different histologic subsets (Table 1). Clinically, the incidence of BRAF mutations is lower in the Asian population (approximately 1%) when compared with the Caucasian population.15,22 The vast majority of BRAF mutations occur in adenocarcinoma and very rarely in squamous cell carcinoma. There is a probable slight female predilection for all BRAF mutations in NSCLC (Table 1), with an average female-to-male ratio of 2 to 1 for the V600E mutation,14,19,22 with the exception of 1 Italian study that reported a dramatically higher female predilection for V600E mutations, with a female-to-male ratio of 9 to 1.17 It is unlikely that ethnic differences account for the variation, because 3 other studies have reported similar findings with distinct patient populations from the United States, Norway, and Japan.14,19,22 One possibility is that there are significant differences in patient characteristics between the Italian group and the others. For instance, a patient population that is dominated by female smokers or females with advanced-stage cancer is likely to result in a higher female-to-male ratio because BRAF V600E mutation correlates with smoking history and possibly more aggressive disease. However, current published results are presented in cohorts, which mask potential differences of patient characteristics across studies.
In contrast to EGFR mutations, BRAF mutations are commonly associated with smoking status (54%-100% of patients with BRAF mutations are current or former smokers).14,15,17-19 Interestingly, it was noted in one report that all non-V600E mutations were found in smokers, whereas V600E mutations occurred more commonly in never-smokers (5% in never-smoker vs 2% in current or former smokers).17 However, the proportion of nonsmokers and/or light smokers did not differ significantly according to the types of BRAF mutations in other case series.15,18
In papillary thyroid cancer, the BRAF V600E mutation is closely related to high-risk clinicopathologic factors such as extrathyroidal invasion, lymph node metastasis, and advanced TNM stage, as well as poorer outcome as evidenced by recurrent and persistent disease.23 The BRAF V600E mutation has also been described as an absolute risk factor for survival in colorectal cancer and melanoma.24 Whether the BRAF mutations carry any prognostic value in NSCLC remain unclear. Currently, BRAF WT and BRAF-mutant NSCLC do not show a difference in overall survival (OS). Because of conflicting results, it is not clear whether the BRAF V600E mutation correlates with poor survival. For example, Marchetti et al17 reported a more aggressive pathology characterized by micropapillary features in V600E-mutated tumors as well as shorter disease-free survival and OS compared with BRAF WT. Cardarella et al18 found a lower response rate and a shorter progression-free survival to platinum-based chemotherapy in BRAF V600E-mutated populations when compared with patients with no V600E mutations; however, this did not reach statistical significance. Conversely, Brustugun et al19 reported no significant difference in OS between BRAF V600E/K and WT populations. Furthermore, a similar finding was described by Kinno et al15 when comparing OS across WT, V600E and non-V600E BRAF populations.
From a pathology standpoint, Yousem et al25 reported a correlation between BRAF V600E mutation and poorer prognosis in lung adenocarcinomas by noting a high prevalence of papillary growth in BRAF V600E cases, which has been associated with a more aggressive clinical course and higher pathologic stage. Immunohistochemical staining of NSCLC tissue samples from 5 patients with BRAF mutations (2 with a V600E mutation, 2 with a D594G mutation, and 1 with a silent mutation) showed higher Ki-67 antigen in 4 of 5 patients, which is also suggestive of higher-grade tumors.22
Therapies for BRAF-Mutated Lung Cancer
At present, there is no FDA-approved treatment for BRAF-mutated NSCLC; however, the National Comprehensive Cancer Network (NCCN) guideline recommends vemurafenib or dabrafenib based on promising clinical data.
Current second-generation BRAF inhibitors, such as vemurafenib and dabrafenib, have been tailored to target the nearly universal BRAF V600 mutation in melanoma. It has potent activity against the V600-mutated BRAF kinases regardless of the type of cancers. There are 2 case reports of patients with BRAF V600E lung adenocarcinoma who responded to vemurafenib26,27 and 1 for dabrafenib.28 Dabrafenib received FDA Breakthrough Therapy Designation for BRAF V600E-mutated NSCLC based on interim analysis from an ongoing phase 2 trial (NCT01336634) published in 2013.29 In that report, 17 patients with BRAF V600E-mutated stage IV NSCLC in whom at least 1 prior line of platinum-containing chemotherapy had failed were given dabrafenib 150 mg orally twice daily. The overall response rate (ORR) and overall disease control rate were 54% and 61%, respectively. The response seemed durable in 2 patients who achieved a partial response and who had received treatment for over a year at the time of the report. This study is ongoing, with the primary outcome being ORR of single-agent dabrafenib versus combination therapy with the MEK inhibitor trametinib.
Despite the success with treatment for BRAF V600 mutations, preclinical data have shown that these selective BRAF inhibitors targeting specific V600 mutations do not display the same antiproliferative effect on lung cancer cell lines harboring activating non-V600 mutations.30 Currently, there is no established treatment for BRAF non-V600 mutations, and there is no evidence in the literature of successful treatment of non-V600 mutations using dabrafenib or vemurafenib. Future design of therapeutics for BRAF V600 and non-V600 mutants now focuses on the molecular components within the Ras-Raf-MEK-ERK pathway, including MEK, CRAF, and MET. Several studies have reported promising results from treating cancers requiring BRAF-dependent activation of the MAPK/ERK pathway.13,16,31-33 Analysis of BRAF V600E-mutated human cell lines, regardless of tissue lineage, has demonstrated a MEK dependency for growth.31 In addition, pharmacologic inhibition of the MEK signaling pathway leads to complete suppression of tumor growth in a mice xenograft.31 Treatment with MEK inhibitors has been demonstrated to induce pronounced tumor regression in lung cancer mouse models bearing tumors with the BRAF V600E mutation.13 Furthermore, NSCLC cell lines with either V600E or non-V600E BRAF mutations were found to be selectively sensitive to MEK inhibition compared with those harboring mutations in EGFR, RAS, or ALK, and ROS kinase fusions as demonstrated by decreased expression of phosphorylated ERK after exposure to a MEK inhibitor.16 Currently, MEK inhibitors are being studied in phase 2 trials as single agents or in combination with BRAF inhibitors (NCT01336634, NCT01362296, NCT00888134, NCT01974258; Table 2). Secondary resistance to BRAF inhibitors inevitably occurs in BRAF V600-mutated cancer, and most of the resistance mechanisms are upstream of MEK and therefore rely on MEK activity.34 It has also been shown that BRAF amplification contributes to resistance of BRAF V600-mutated colorectal cell lines to MEK inhibitors, and that combined MEK and BRAF inhibition was able to overcome resistance to either inhibitor alone.35 Because of the additive benefit of MEK inhibitors to enhance tumor inhibition and delay acquiring secondary resistance, combination therapy with BRAF inhibitors and MEK inhibitors is currently being studied and could become the trend in the future for the treatment of NSCLC with BRAF V600 mutations.
MET belongs to the family of membrane receptor tyrosine kinases. Activation of MET can turn on a number of oncogenic pathways, including the Ras-Raf-MEK-ERK pathway. It has been shown in vitro that innate resistance to BRAF inhibitors is elicited by stromal cells in the tumor microenvironment via hepatocyte growth factor (HGF) secretion and subsequent MET activation, and that dual inhibition of RAF plus HGF or MET resulted in reversal of drug resistance.36 Pharmacologic inhibition of MET can be achieved using onartuzumab, a humanized monovalent monoclonal antibody directed against the extracellular domain of MET, thereby preventing the binding of its ligand, HGF. Currently, the MET inhibitor is being investigated in combination with a BRAF inhibitor, a MEK inhibitor, or both (NCT01974258).
Cyclin-dependent kinases (CDKs) belong to an important family of protein kinases that regulate critical cellular processes such as cell cycle, transcription, and mRNA processing. The development of a class of highly specific and orally bioavailable inhibitors of CDK4/6 has shown promising preclinical results when used in combination with other targeted therapies. By inhibiting the activation of CDK4/6, these drugs suppress the growth of tumor cells by blocking CDK-dependent phosphorylation of retinoblastoma protein, which leads to cell cycle arrest. When combined with LGX818 (a BRAF V600E inhibitor), LEE001 (a CDK inhibitor) has shown antitumor activity in melanoma models harboring activating BRAF mutations, even in melanoma models that are resistant to LGX818.37 The synergistic effect can be explained by CDK also working as a common downstream effector molecule of the MAPK/ERK signaling pathway. Currently, the CDK inhibitor is being studied as part of a triple therapy with a BRAF and MEK inhibitor (NCT01543698).
Dasatinib is a multikinase inhibitor most commonly used in hematologic malignancies to target the BCR-ABL fusion protein. It was initially designed in a clinical trial38 to be used as first-line treatment for metastatic NSCLC for its Src family kinases (SFKs) inhibition property because elevated levels of activated SFKs are commonly seen in NSCLC39,40 and because SFKs play an important role in multiple processes, including angiogenesis, invasion, proliferation, and survival of cancer cells.41 The results from this clinical trial showed that the overall disease control rate was not superior to the historical response to standard chemotherapy. However, for the single patient who had a partial response after 12 weeks of treatment, the response was durable, and he had no evidence of disease 4 years after treatment.38 Subsequently, the patient’s tumor tissue was analyzed, and a kinase-inactivating BRAF mutation (BRAF Y472C) was found.42 Inactivating BRAF mutations has been demonstrated to activate the MAPK/ERK signaling pathway by activation of CRAF via heterodimerization.12,32,43 Sen et al42 discovered that dasatinib selectively induces irreversible senescence and cell cycle arrest in NSCLC bearing kinase-inactivating BRAF mutations. Although the precise mechanism of dasatinib-induced senescence and apoptosis in NSCLC remains unknown, current data support a role of BRAF-CRAF heterodimerization in sensitivity to dasatinib. A clinical trial targeting kinase-inactivating BRAF-mutant NSCLC (NCT01514864) is under way.
Both vemurafenib and dabrafenib, as single agents, have shown high efficacy to inhibit MEK activity caused by the highly active BRAF V600E mutation. However, the MAPK/ERK signaling pathway can be activated by alternate pathways despite drug-mediated inhibition of activating BRAF mutants, resulting in secondary drug resistance. The knowledge of acquired resistance to BRAF V600 inhibitors comes largely from studies in melanoma. Multiple secondary resistance mechanisms have been described, and they can be separated as either ERK dependent or non-ERK dependent.34,44 ERK-dependent mechanisms are much more common and are usually associated with reactivation of the MAPK pathway via alternate pathways or upregulation of the signaling components in the MAPK pathway. Some of the ERK-dependent mechanisms include BRAF amplification or introduction of splice variants, upregulation of receptor tyrosine kinases, and acquired mutation in RAS.28,34,44 A number of therapies are being investigated to overcome secondary resistance, including combining BRAF V600 inhibitors with MEK and ERK inhibitors (Table 2).45,46
Paradoxical activation of the MAPK/ERK pathway on treatment with BRAF V600 inhibitors is well described.20,21 It has been shown in multiple systems, including human melanoma cell lines and tumor xenografts, that in the presence of oncogenic RAS mutations, BRAF V600E inhibitors lead to activation of CRAF by increasing WT and kinase-inactivating BRAF binding to CRAF to form heterodimers, which result in potentiated MAPK/ERK signaling. A new generation of RAF inhibitors called “paradox breakers,” including PLX8394 (NCT02012231) and PLX7904, are in development. The paradox breakers do not elicit paradoxical activation and therefore potentially reduce the side effects of secondary cutaneous malignancies. In addition, they have also been shown to have inhibitory effects in vemurafenib-resistant melanoma cells with mutated RAS47 or BRAF V600E splice variants.48
BRAF mutations have been identified in various cancers and are considered to be the driver mutations for approximately 1% to 5% of NSCLCs. The most common mutation reported is the activating BRAF V600E mutation. In contrast to melanoma, of which almost all result from BRAF V600E mutation, NSCLCs harbor a variety of BRAF mutations, some of which are kinase inactivating but still capable of activating the MAPK/ERK pathway through transactivation of CRAF. BRAF mutations are more commonly found in patients with a history of smoking, and there may be a slight female predominance. Although some studies describe a correlation between BRAF V600E mutations with more aggressive pathologic features, the question of whether BRAF mutations carry any prognostic value is still up for debate. Currently, there is no FDA-approved treatment for BRAF-mutated NSCLC; however, BRAF V600 inhibitors are recommended by the NCCN guideline for patients with tumors harboring sensitive BRAF mutations. Investigation of combination therapies is under way to achieve a better response to therapy and to overcome secondary resistance.
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Dr Yeh received her medical degree from the National Cheng-Kung University, Taiwan, and is currently practicing as a second-year fellow in the Division of Hematology/Oncology at the University of California, San Diego (UCSD).
Dr Bazhenova is Associate Clinical Professor of Medicine in the Division of Hematology/Oncology and is Medical Director of the UCSD Moores Cancer Center Infusion Center. Her clinical practice and research concentrate on lung cancer, particularly as it relates to females and nonsmokers. She actively participates in cooperative group trials and takes an active role in designing and implementing clinical investigations, including phase 2 studies and correlative science projects with several UCSD investigators.
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