Scaffold KSR2 overexpression is associated with melanoma A375 cells resistance to Vemurafenib
0
Citation
0
Reference
20
Related Paper
Abstract:
A large number of tumors shows a deregulation of the pathway RAS-RAF-MEK-ERK. Most of cases of melanoma are caused by the mutation V600E of BRAF, that leads to the constitutive activation of this kinase and of the MAPK pathway. One of the most important BRAF V600E inhibitor used against melanoma is vemurafenib.Extension study of melanoma patients with BRAF V600E tumors shows that vemurafenib treatment of these metastatic melanomas causes complete or partial tumor regression. However, the majority of patients eventually develops resistance or presents intrinsic resistance against this drug, and the tumor becomes more aggressive.Several mechanisms of resistance to BRAF inhibitors have been described. In most of these mechanisms the resistance to BRAF inhibitors results from reactivation of MEK-ERK pathway. Scaffold KSR2 is an important modulator of ERK-MAPK signalling pathway. In this study, we investigated the role of KSR2 in vemurafenib-treated melanoma cells.We found that treatment with the BRAF-selective inhibitor vemurafenib induced the expression of KSR2 in A375 human melanoma cells. Interestingly, the KSR2 overexpression increased the melanoma cells growth after treatment with vemurafenib. These results suggest that scaffold KSR2 could play an important role in the mechanism of resistance of melanoma against BRAF inhibitor vemurafenib.Keywords:
V600E
Cite
Cite
Citations (0)
A preclinical study provides the rationale for combining BRAF-targeted therapy with immunotherapy agents in patients with BRAF mutations. These mutations activate the MAPK signaling pathway, which leads to increased oncogenic potential. The researchers showed that in BRAF-mutant melanoma cell lines, a selective BRAF inhibitor (PLX4720) blocked the MAPK pathway and increased tumor antigen expression without affecting T-cell function.
Targeted Therapy
Cite
Citations (0)
Abstract Activating mutations in BRAF (BRAFV600E) occur in ~10% of colorectal cancers (CRCs) and drive tumorigenesis through constitutive activation of MAPK signaling. In metastatic CRC, BRAF mutations are associated with poorer prognosis and resistance to conventional therapies, necessitating an urgent need to develop new treatments for these patients. BRAF inhibitors such as vemurafenib and dabrafenib have significant clinical activity in BRAF-mutant melanoma, however BRAF-mutant CRCs are largely refractory to these agents, due at least in part to feedback-relief mediated reactivation of MAPK signaling or alternate signaling pathway activation. Strategies to enhance the activity of BRAF inhibitors in BRAF-mutant CRC are therefore needed. Consistent with clinical observations, treatment of a panel of BRAF-mutant melanoma and CRC cell lines with vemurafenib resulted in significantly increased apoptosis in melanoma cell lines compared to CRC cell lines, where effects were largely cytostatic. To determine the mechanisms for this differential response we interrogated vemurafenib-induced gene expression changes in the two tumor types, focusing on altered expression of components of the intrinsic apoptotic pathway. Vemurafenib induced a more pronounced increase in expression of the pro-apoptotic genes BIM, BMF and PUMA and suppression of pro-survival gene MCL1 in melanoma cells compared to CRC cells. These findings suggested that the extent to which expression of pro and anti-apoptotic genes are altered by vemurafenib in CRC cells may be insufficient to reach the threshold required for apoptosis initiation. We therefore postulated that BH3-mimetics may synergize with vemurafenib to induce apoptosis in BRAF-mutant CRC cells. Analysis of quantitative proteomic data of BRAF-mutant CRC cell lines revealed significantly higher basal expression of the pro-survival proteins Bcl-xL and MCL1 compared to BCL2 and BCLW, suggesting CRC cells may be particularly dependent on Bcl-xL and MCL1 for survival. Indeed, combination treatment of BRAF-mutant CRC cells with the Bcl-xL inhibitor A-1331852 significantly enhanced apoptosis in the majority of BRAF-mutant CRC lines. Comparatively, combination treatment of vemurafenib with the MCL1 inhibitor S63845 induced a modest increase in apoptosis, while combination treatment with the BCL2 inhibitor ABT-199 had no effect on apoptosis, consistent with the low levels of BCL2 expression in these lines. Finally, we investigated the effect of combination treatment of vemurafenib with inhibitors of both Bcl-xL and MCL1. The triple combination further enhanced apoptosis in 3/5 cell lines, suggesting these cell lines are likely dependent on both Bcl-xL and MCL1 for survival. Collectively, these findings demonstrate that combining BRAF-inhibitors with Bcl-xL and/or MCL1 inhibitors may represent a novel strategy for treating BRAF-mutant CRC. Citation Format: Laura J. Jenkins, Fiona Chionh, Ian Y. Luk, Erinna F. Lee, Amardeep S. Dhillon, Niall Tebbutt, Walter D. Fairlie, John M. Mariadason. BRAF inhibitors synergize with BH3 mimetics to induce apoptosis in BRAF mutant colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2492.
MCL1
Dabrafenib
V600E
Puma
Cite
Citations (0)
Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF(V600E) inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF(V600E) mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF(V600E) provided combinatorial benefit in vemurafenib-sensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF(V600E) by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAF(V600E)-driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors.
Hsp90 inhibitor
Cite
Citations (93)
Targeted Therapy
Cite
Citations (1)
Targeted Therapy
Cite
Citations (192)
Acquired resistance
Cite
Citations (81)
Aberrant activation of the BRAF kinase occurs in ∼60% of melanomas, and although BRAF inhibitors have shown significant early clinical success, acquired resistance occurs in most patients. Resistance to chronic BRAF inhibition often involves reactivation of mitogen-activated protein kinase (MAPK) signaling, and the combined targeting of BRAF and its downstream target MAPK/ERK kinase (MEK) may delay or overcome resistance. To investigate the efficacy of combination BRAF and MEK inhibition, we generated melanoma cell clones resistant to the BRAF inhibitor GSK2118436. These BRAF inhibitor-resistant sublines acquired resistance through several distinct mechanisms, including the acquisition of activating N-RAS mutations and increased accumulation of COT1. These alterations uniformly promoted MAPK reactivation and most conferred resistance to MEK inhibition and to the concurrent inhibition of BRAF and MEK. These data indicate that melanoma tumors are likely to develop heterogeneous mechanisms of resistance, many of which will confer resistance to multiple MAPK inhibitory therapies.
Acquired resistance
Cite
Citations (84)
Abstract Targeting mutant BRAF in patients with melanomas harboring this oncogene has been highly successful as a first-line treatment, but other mutations may affect its efficacy and alter the route of acquired resistance resulting in recurrence and poor prognosis. As an evolving strategy, melanoma treatment needs to be expanded to include targets based on newly discovered emerging molecules and pathways. We here show that PERK plays a critical role in BRAF inhibitor-acquired resistance in melanoma with impaired PTEN. Inhibition of PERK by either shRNA or a pharmacological inhibitor blocked the growth of BRAF inhibitor-resistant melanoma with impaired PTEN in vitro and in vivo, suggesting an effective approach against melanomas with mutant BRAF and PTEN deficiency. Our current findings, along with our previous discovery that the AXL/AKT axis mediates resistance to BRAF inhibition in melanoma with wild-type PTEN, provide new insights toward a strategy for combating BRAF inhibition-acquired resistance in BRAF mutant melanoma with different PTEN statuses.
Cite
Citations (12)
The advent of mitogen-activated protein kinase (MAPK) inhibitors that directly inhibit tumor growth and of immune checkpoint inhibitors (ICI) that boost effector T cell responses have strongly improved the treatment of metastatic melanoma. In about half of all melanoma patients, tumor growth is driven by gain-of-function mutations of BRAF (v-rat fibrosarcoma (Raf) murine sarcoma viral oncogene homolog B), which results in constitutive ERK activation. Patients with a BRAF mutation are regularly treated with a combination of BRAF and MEK (MAPK/ERK kinase) inhibitors. Next to the antiproliferative effects of BRAF/MEKi, accumulating preclinical evidence suggests that BRAF/MEKi exert immunomodulatory functions such as paradoxical ERK activation as well as additional effects in non-tumor cells. In this review, we present the current knowledge on the immunomodulatory functions of BRAF/MEKi as well as the non-intended effects of ICI and discuss the potential synergistic effects of ICI and MAPK inhibitors in melanoma treatment.
Cite
Citations (18)