<scp>RAC</scp>1 P29S regulates <scp>PD</scp>‐L1 expression in melanoma

Vu, Ha Linh; Rosenbaum, Sheera; Purwin, Timothy J.; Davies, Michael A.; Aplin, Andrew E.

doi:10.1111/pcmr.12392

Cited by 64 publications

(65 citation statements)

References 39 publications

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“…Rac1 overexpression has been found in various types of cancer, such as lung cancer, gastric cancer, pancreatic cancer, bladder cancer and breast cancer 43, 44, 45, 46, 47. Moreover, activation of Rac1 can increase cancer cell migration, adhesion, invasion, proliferation and metastasis 40, 44, 48, 49, 50. In our previous study, we found that miR‐124 repressed osteosarcoma cell proliferation, migration and invasion by targeting Rac1 expression 34.…”

Section: Discussionmentioning

confidence: 99%

Retracted: MicroRNA‑224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1

Geng

Fang

et al. 2016

J Cellular Molecular Medi

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Osteosarcoma is the most common primary bone tumour in children and adolescents. Accumulating evidence has shown that microRNAs (miRNAs) participate in the development of almost all types of cancer. Here, we investigated the role of miR‐224 in the development and progression of osteosarcoma. We demonstrated that miR‐224 was down‐regulated in osteosarcoma cell lines and tissues. Lower miR‐224 levels were correlated with shorter survivalin osteosarcoma patients. Furthermore, overexpression of miR‐224 suppressed osteosarcoma cell proliferation, migration and invasion and contributed to the increased sensitivity of MG‐63 cells to cisplatin. We identified Rac1 as a direct target gene of miR‐224 in osteosarcoma. Rac1 expression was up‐regulated in the osteosarcoma cell lines and tissues, and there was an inverse correlation between Rac1 and miR‐224 expression in osteosarcoma tissues. Furthermore, rescuing Rac1 expression decreased the sensitivity of miR‐224‐overexpressing MG‐63 cells to cisplatin. We also demonstrated that ectopic expression of Rac1 promoted the proliferation, migration and invasion of miR‐224‐overexpressing MG‐63 cells. These data suggest that miR‐224 plays a tumour suppressor role in the development of osteosarcoma and is related to the sensitivity of osteosarcoma to cisplatin.

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Section: Discussionmentioning

confidence: 99%

Retracted: MicroRNA‑224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1

Geng

Fang

et al. 2016

J Cellular Molecular Medi

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“…This mutation confers resistance to Raf and MEK inhibitors, thus having significant clinical therapeutic significance (20). Interestingly, expression of Rac1 P29S in melanoma patients correlates with PD-L1 up-regulation, thus potentially contributing to suppression of an anti-tumor immune response (21). These findings could also be extended to other cancers since the Rac1 P29S hotspot mutation has been identified in head and neck, and endometrial cancers (22).…”

Section: Emerging Paradigms In Rho Gtpase Hyperactivation In Cancermentioning

confidence: 99%

“…In addition to the potential role for Rac1 in the control of PD-L1 expression and suppression of anti-tumor immune responses described above (21), it is becoming increasingly evident that Rac1 is involved in acquired resistance. Ectopic expression of Rac1 GEFs, Rac1 activators such as BCAR3/AND-34, or constitutively active Rac1, promotes resistance to anti-estrogens, a widely used endocrine therapeutic approach for estrogen receptor-positive (ER+) breast cancer patients (57,58).…”

Section: Targeting Rac Gtpases: Can We Overcome Therapy Resistance?mentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.

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“…The Rac-GEF DOCK1 has recently been demonstrated as a critical regulator of the malignant phenotypes induced by Rac1 P29S (41). From a pharmacological standpoint, the Rac1 P29S mutation is associated with resistance to Raf inhibitors and PD-L1 up-regulation, thus contributing to evading immune surveillance and potentially serving as a predictive biomarker for therapy resistance in melanoma (42, 43). A recent interesting study revealed that Rac1 mutant melanoma cells are highly sensitive to Pak inhibition, a result consistent with the augmented engagement of Rac effectors by the Rac1 P29S mutant (44).…”

Section: Aberrant Rac Expression and Activity In Human Cancermentioning

confidence: 99%

“…As indicated above, Rac1 P29S mutated melanoma cells are resistant to clinical BRAF inhibitors but highly sensitive to Pak inhibition (42, 44), and they exhibit elevated expression of PD-L1, a ligand of the checkpoint protein PD-1 that plays a fundamental role in immune evasion (43). Conceivably, pharmacological inhibition of Rac could be beneficial in combination with anti-PD-L1 monoclonal antibodies or other immune checkpoint inhibitors.…”

Section: Concluding Remarks - Rac and Tumor Susceptibility: From Biocmentioning

confidence: 99%

The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

Casado‐Medrano

Baker

López‐Haber

et al. 2018

Biochemical Society Transactions

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The family of Rho GTPases are involved in the dynamic control of cytoskeleton reorganization and other fundamental cellular functions, including growth, motility, and survival. Rac1, one of the best characterized Rho GTPases, is an established effector of receptors and an important node in signaling networks crucial for tumorigenesis and metastasis. Rac1 hyperactivation is common in human cancer, and could be the consequence of overexpression, abnormal upstream inputs, deregulated degradation, and/or anomalous intracellular localization. More recently, cancer associated gain-of-function mutations in Rac1 have been identified which contribute to tumor phenotypes and confer resistance to targeted therapies. Deregulated expression/activity of Rac Guanine nucleotide Exchange Factors (GEFs) responsible for Rac activation has been largely associated to a metastatic phenotype and drug resistance. Translating our extensive knowledge in Rac pathway biochemistry into a clinical setting still remains a major challenge, nonetheless remarkable opportunities for cancer therapeutics arise from promising lead compounds targeting Rac and its effectors.

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RAC1 P29S regulates PD‐L1 expression in melanoma

Cited by 64 publications

References 39 publications

Retracted: MicroRNA‑224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1

Retracted: MicroRNA‑224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

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