Dual MAPK/CDK Targeting in Melanoma: New Approaches, New Challenges

Sullivan, Ryan J.

doi:10.1158/2159-8290.cd-18-0224

Cited by 8 publications

(6 citation statements)

References 10 publications

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“…Furthermore, survival analysis showed that C2 had a better prognosis than the other subtypes. In the GSEA, in addition to enrichment for immune-related pathways, the C2 subtype was enriched for many pathways closely related to the occurrence, development, and metastasis of cancer, such as apoptosis, cell adhesion, and focal adhesion, as well as JAK-STAT and MAPK signaling pathways (22)(23)(24)(25)(26)(27). Activation point mutations of FGFR3 are found in up to 80% of low-grade and staged urothelial carcinomas (UC) of the bladder (28).…”

Section: Discussionmentioning

confidence: 99%

Identification of Four Immune Subtypes in Bladder Cancer Based on Immune Gene Sets

Tang

Liu

et al. 2020

Front. Oncol.

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Molecular classification of bladder cancer is becoming increasingly important for its clinical management. And, the current classifications are primarily based on gene expression profiles. We identified four immunotypes of bladder cancer (referred to as C1-C4) based on gene expression profiles performed by immune-related gene sets in three independent data sets, and proved that this classification is effective and reproducible. We found that C2 is an immune-infiltrating type and C4 is an immune "desert" type. These types are characterized by the up-and downregulation of genes encoding numerous immune checkpoint proteins and HLA and regulating human immune cell subgroups. The survival rate was better for the C2 subtype than for other subtypes. We believe that this can be explained by the antitumor effects of CD4 memory T cells and CD8 T cells as well as their ability to circumvent M0 macrophage antitumor immunity. In addition, C2 was most sensitive to not only anti-PD-1 immunosuppressive therapy, but also conventional chemotherapeutics such as gemcitabine and bleomycin. The C4 subtype was most sensitive to the chemotherapy drugs cisplatin and doxorubicin. This theoretical framework may guide the personalized treatment of bladder cancer in the future. It is worth noting that the C2 immune infiltration type positively correlates with a variety of stromal components, such as enrichment of endothelial cells and fibroblasts, epithelial-mesenchymal transition, and angiogenesis, together with enrichment of seven kinds of stem cells. We further identified tumor-related JAK-STAT and other signaling pathways in the C2 subtype, along with important mutations in the proteins involved in these pathways, revealing the complex mechanism underlying tumor immune escape. Our results, and particularly the identification of hub genes specific to the C2 and C4 subtypes, provide a reference for the development of immunotherapeutic agents against bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Identification of Four Immune Subtypes in Bladder Cancer Based on Immune Gene Sets

Tang

Liu

et al. 2020

Front. Oncol.

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“…The experimental results showed that SGK1 inhibition significantly decreased pERK1/2 (activated form) expression, and there was no significant difference in the total amount between the two groups. Moreover, SGK1i and RAF→MEK pathway inhibitors synergistically repress the ERK1/2 pathway, along with proliferation of RKO and HT29 cells (19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Mechanism 3: Sgk1 May Be the Downstream Target Gene Of Yap Transcriptional Activation Yap Positively Regulates The Downstream Tamentioning

confidence: 97%

Yes-activated protein promotes primary resistance of BRAF V600E mutant metastatic colorectal cancer cells to mitogen-activated protein kinase pathway inhibitors

Su¹,

Zhan²,

Zhang³

et al. 2021

J Gastrointest Oncol

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Background: Most colorectal cancer (CRC) patients with the BRAF V600E mutation display resistance to chemotherapy and targeted medicinal treatments. Thus, exploring new drugs and drug resistance mechanisms for the BRAF V600E mutation has become an urgent clinical priority. Methods: MTS experiment, cell cloning experiment, cell scratching experiment, Transwell experiment, chromatin immunoprecipitation (ChIP), quantitative polymerase chain reaction (qPCR) and flow cytometry are used. Detect the transcription and protein expression of YAP in colorectal cancer cell lines, establish a transient cell line with YAP gene overexpression and knockdown, and detect the effect of YAP gene expression on the biological functions of colorectal cancer cells RKO and HT-29. And further study the mechanism of YAP regulating the response of RAF and MEK targeted therapy.Results: In this study, for the first time, we verified that the expression of transcription factor yes-associated protein (YAP) was upregulated in BRAF V600E mutant CRC cells. After knocking down YAP, we observed a reduction in the growth rate, proliferation, and invasion ability of colon cancer cells. We further verified that YAP knockdown increased sensitivity of BRAF V600E mutant CRC cells to mitogen-activated protein kinase (MAPK) pathway inhibitors. In addition, we clarified the mechanism underlying YAP regulation of RAF and MAPK/extracellular signal-regulated kinase (MEK)-targeted therapy response: YAP cooperates with RAF→MEK pathway inhibitors to regulate the cell cycle, increase cell G1/S phase arrest, and increase apoptosis.Conclusions: These results suggest that YAP expression may be related to the primary resistance of MAPK inhibitors in metastatic CRC with the BRAF V600E mutation. Therefore, the combination of YAP and MAPK pathway inhibitors in BRAF V600E mutant metastatic CRC may present a promising treatment method.

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“…The MEK inhibitor strategy is also applicable for breast cancer patients receiving inhibitors of CDK4/6 due to exhibiting MAPK‐related resistance to CDK inhibitor therapy (de Leeuw et al, ). In NRAS mutant melanoma patients receiving dual MEK/CDK4/6 inhibitors, acquired resistance to the PI3K effector S6K1 may occur that confers drug resistance (Romano et al, ), requiring convergence of MEK/CDK inhibitors with suppressors of PI3K pathway's mediators such as S6K to overcome this resistance (Sullivan, ).…”

Section: Mapk In Cancer Growth and Drug Resistancementioning

confidence: 99%

“…Class III BRAF mutants are RAS dependent, so they are sensitive to RAS inhibitors, while classes I and II are RAS independent requiring other mechanisms for dissecting MAPK signaling in tumors harboring these mutants (Yao et al, ). BRAF/MEK inhibition is suggested for class I BRAF mutant cancers, and MEK/ERK inhibition is suggested for non‐class I BRAF mutant cancers (Sullivan, ). For BRAF L597S mutant melanoma, dual MAPK suppression with BRAF/MEK inhibitors is promising to improve survival of affected patients (Dankner et al, ).…”

Section: Combination Therapy Is a Promising Strategy For Targeting Mamentioning

confidence: 99%

“…In KRAS mutant cancers, for example, a recent study attested that CRAF ablation could cause cancer regression without influencing MAPK signaling and without exerting conspicuous systemic toxicity (McCormick, ). To minimize toxicities and to maximize the efficacy of therapy it is better to use suboptimal concentrations of target inhibitors (Caumanns et al, ) and to apply a schedule escalation of drug dosages for reducing upward titrating of drugs and related toxicities (Sullivan, ). To reach this purposes, it is necessary to first determine specific mutations in the MAPK pathway and the rate of sensitivity to kinase inhibitors.…”

Section: Combination Therapy Is a Promising Strategy For Targeting Mamentioning

confidence: 99%

See 1 more Smart Citation

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Najafi

Ahmadi

Mortezaee

2019

Cell Biology International

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Mitogen-activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal-epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular-signal-regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross-talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase-2, transforming growth factor-β, NOTCH and (in particular) with phosphatidylinositol 3-kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK-targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre-evaluation of cancer-type-specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need.

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Dual MAPK/CDK Targeting in Melanoma: New Approaches, New Challenges

Cited by 8 publications

References 10 publications

Identification of Four Immune Subtypes in Bladder Cancer Based on Immune Gene Sets

Identification of Four Immune Subtypes in Bladder Cancer Based on Immune Gene Sets

Yes-activated protein promotes primary resistance of BRAF V600E mutant metastatic colorectal cancer cells to mitogen-activated protein kinase pathway inhibitors

Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

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