scholarly journals The c-Jun/RHOB/AKT pathway confers resistance ofBRAF-mutant melanoma cells to MAPK inhibitors

Oncotarget ◽  
2015 ◽  
Vol 6 (17) ◽  
pp. 15250-15264 ◽  
Author(s):  
Audrey Delmas ◽  
Julia Cherier ◽  
Magdalena Pohorecka ◽  
Claire Medale-Giamarchi ◽  
Nicolas Meyer ◽  
...  
Keyword(s):  
Melanoma Cells ◽  
Akt Pathway ◽  
Mapk Inhibitors

scholarly journals Targeting Genome Stability in Melanoma—A New Approach to an Old Field

2021 ◽  
Vol 22 (7) ◽  
pp. 3485
Author(s):  
Marta Osrodek ◽  
Michal Wozniak
Keyword(s):  
Genome Stability ◽  
Genome Instability ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Rapid Development ◽  
Melanoma Cells ◽  
Old Field ◽  
Number Of Patients ◽  
Recent Developments ◽  
Mapk Inhibitors

Despite recent groundbreaking advances in the treatment of cutaneous melanoma, it remains one of the most treatment-resistant malignancies. Due to resistance to conventional chemotherapy, the therapeutic focus has shifted away from aiming at melanoma genome stability in favor of molecularly targeted therapies. Inhibitors of the RAS/RAF/MEK/ERK (MAPK) pathway significantly slow disease progression. However, long-term clinical benefit is rare due to rapid development of drug resistance. In contrast, immune checkpoint inhibitors provide exceptionally durable responses, but only in a limited number of patients. It has been increasingly recognized that melanoma cells rely on efficient DNA repair for survival upon drug treatment, and that genome instability increases the efficacy of both MAPK inhibitors and immunotherapy. In this review, we discuss recent developments in the field of melanoma research which indicate that targeting genome stability of melanoma cells may serve as a powerful strategy to maximize the efficacy of currently available therapeutics.

scholarly journals T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells

2020 ◽  
Vol 122 (7) ◽  
pp. 1023-1036 ◽  
Author(s):  
Karol Granados ◽  
Laura Hüser ◽  
Aniello Federico ◽  
Sachindra Sachindra ◽  
Gretchen Wolff ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Melanoma Cells ◽  
Channel Inhibition ◽  
Mapk Inhibitors

scholarly journals Human melanoma cells resistant to MAPK inhibitors can be effectively targeted by inhibition of the p90 ribosomal S6 kinase

Oncotarget ◽  
2017 ◽  
Vol 8 (22) ◽  
pp. 35761-35775 ◽  
Author(s):  
Corinna Kosnopfel ◽  
Tobias Sinnberg ◽  
Birgit Sauer ◽  
Heike Niessner ◽  
Anja Schmitt ◽  
...  
Keyword(s):  
Melanoma Cells ◽  
Human Melanoma ◽  
S6 Kinase ◽  
Human Melanoma Cells ◽  
P90 Ribosomal S6 Kinase ◽  
Mapk Inhibitors ◽  
Ribosomal S6 Kinase

scholarly journals Melanoma cells resistant towards MAPK inhibitors exhibit reduced TAp73 expression mediating enhanced sensitivity to platinum-based drugs

2018 ◽  
Vol 9 (9) ◽  
Author(s):  
Elena Makino ◽  
Vanessa Gutmann ◽  
Corinna Kosnopfel ◽  
Heike Niessner ◽  
Andrea Forschner ◽  
...  
Keyword(s):  
Melanoma Cells ◽  
Enhanced Sensitivity ◽  
Mapk Inhibitors

scholarly journals CD133 Is Associated with Increased Melanoma Cell Survival after Multikinase Inhibition

2019 ◽  
Vol 2019 ◽  
pp. 1-19 ◽  
Author(s):  
Cynthia M. Simbulan-Rosenthal ◽  
Anirudh Gaur ◽  
Hengbo Zhou ◽  
Maryam AbdusSamad ◽  
Qing Qin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Kinase Inhibitors ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Melanoma Cells ◽  
Stem Cell Marker ◽  
High Dose ◽  
Recurrence Rates ◽  
Mapk Inhibitors

FDA-approved kinase inhibitors are now used for melanoma, including combinations of the MEK inhibitor trametinib, and BRAF inhibitor dabrafenib for BRAFV600 mutations. NRAS-mutated cell lines are also sensitive to MEK inhibitionin vitro, and NRAS-mutated tumors have also shown partial response to MEK inhibitors. However, melanoma still has high recurrence rates due to subpopulations, sometimes described as “melanoma initiating cells,” resistant to treatment. Since CD133 is a putative cancer stem cell marker for different cancers, associated with decreased survival, we examined resistance of patient-derived CD133(+) and CD133(-) melanoma cells to MAPK inhibitors. Human melanoma cells were exposed to increasing concentrations of trametinib and/or dabrafenib, either before or after separation into CD133(+) and CD133(-) subpopulations. In parental CD133-mixed lines, the percentages of CD133(+) cells increased significantly (p<0.05) after high-dose drug treatment. Presorted CD133(+) cells also exhibited significantly greater (p<0.05) IC50s for single and combination MAPKI treatment. siRNA knockdown revealed a causal relationship between CD133 and drug resistance. Microarray and qRT-PCR analyses revealed that ten of 18 ABC transporter genes were significantly (P<0.05) upregulated in the CD133(+) subpopulation, while inhibition of ABC activity increased sensitivity, suggesting a mechanism for increased drug resistance of CD133(+) cells.

Luteolin inhibits proliferation and induces apoptosis of human melanoma cells in vivo and in vitro by suppressing MMP-2 and MMP-9 through the PI3K/AKT pathway

2019 ◽  
Vol 10 (2) ◽  
pp. 703-712 ◽  
Author(s):  
Xin Yao ◽  
Wei Jiang ◽  
Danhong Yu ◽  
Zhaowei Yan
Keyword(s):  
Malignant Melanoma ◽  
Incidence Rate ◽  
Melanoma Cell ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Akt Pathway ◽  
Human Melanoma Cells ◽  
Cell Metastasis

Since the incidence rate of malignant melanoma is increasing annually, development of drugs against melanoma cell metastasis has become more urgent.

scholarly journals Regulation of Melanogenesis through Phosphatidylinositol 3-Kinase-Akt Pathway in Human G361 Melanoma Cells

2000 ◽  
Vol 115 (4) ◽  
pp. 699-703 ◽  
Author(s):  
Masahiro Oka ◽  
Hiroshi Nagai ◽  
Hideya Ando ◽  
Mizuho Fukunaga ◽  
Miyoko Matsumura ◽  
...  
Keyword(s):  
Melanoma Cells ◽  
Akt Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals In vitro long-term treatment with MAPK inhibitors induces melanoma cells with resistance plasticity to inhibitors while retaining sensitivity to CD8 T cells

2017 ◽  
Vol 37 (3) ◽  
pp. 1367-1378 ◽  
Author(s):  
Florencia Paula Madorsky Rowdo ◽  
Antonela Barón ◽  
Erika María Von Euw ◽  
José Mordoh
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Melanoma Cells ◽  
Term Treatment ◽  
Long Term Treatment ◽  
Mapk Inhibitors

scholarly journals Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation

2022 ◽  
Vol 8 (1) ◽  
pp. a006140
Author(s):  
Florence Choo ◽  
Igor Odinstov ◽  
Kevin Nusser ◽  
Katelyn S. Nicholson ◽  
Lara Davis ◽  
...  
Keyword(s):  
Spindle Cell ◽  
Treatment Options ◽  
Akt Pathway ◽  
Biological Entity ◽  
Oncogenic Signaling ◽  
Gain Of Function ◽  
Functional Impact ◽  
Oncogenic Mutation ◽  
Patient Specimen ◽  
Mapk Inhibitors

Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a rare subtype of rhabdomyosarcoma, commonly harboring a gain-of-function L122R mutation in the muscle-specific master transcription factor MYOD1. MYOD1-mutated ssRMS is almost invariably fatal, and development of novel therapeutic approaches based on the biology of the disease is urgently needed. MYOD1 L122R affects the DNA-binding domain and is believed to confer MYC-like properties to MYOD1, driving oncogenesis. Moreover, the majority of the MYOD1-mutated ssRMS harbor additional alterations activating the PI3K/AKT pathway. It is postulated that the PI3K/AKT pathway cooperates with MYOD1 L122R. To address this biological entity, we established and characterized a new patient-derived ssRMS cell line OHSU-SARC001, harboring MYOD1 L122R as well as alterations in PTEN, PIK3CA, and GNAS. We explored the functional impact of these aberrations on oncogenic signaling with gain-of-function experiments in C2C12 murine muscle lineage cells. These data reveal that PIK3CAI459_T462del, the novel PIK3CA variant discovered in this patient specimen, is a constitutively active kinase, albeit to a lesser extent than PI3KCAE545K, a hotspot oncogenic mutation. Furthermore, we examined the effectiveness of molecularly targeted PI3K/AKT/mTOR and RAS/MAPK inhibitors to block oncogenic signaling and suppress the growth of OHSU-SARC001 cells. Dual PI3K/mTOR (LY3023414, bimiralisib) and AKT inhibitors (ipatasertib, afuresertib) induced dose-dependent reductions in cell growth. However, mTOR-selective inhibitors (everolimus, rapamycin) alone did not exert cytotoxic effects. The MEK1/2 inhibitor trametinib did not impact proliferation even at the highest doses tested. Our data suggest that molecularly targeted strategies may be effective in PI3K/AKT/mTOR-activated ssRMS. Taken together, these data highlight the importance of utilizing patient-derived models to assess molecularly targetable treatments and their potential as future treatment options.

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