Genetic Profiling of Advanced Melanoma: Candidate Mutations for Predicting Sensitivity and Resistance to Targeted Therapy

Olbryt, Magdalena; Pigłowski, Wojciech; Rajczykowski, Marcin; Pfeifer, Aleksandra; Student, Sebastian; Fiszer-Kierzkowska, Anna

doi:10.1007/s11523-020-00695-0

Cited by 22 publications

(15 citation statements)

References 47 publications

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“…Advances in genetic analytical techniques, such as next generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR) have considerably expanded our knowledge of the genetic changes involved in BRAF inhibitor resistance, and raise the possibility of incorporating mutational information into predictive or prognostic models [ 10 , 11 , 12 ].…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Proietti

Skroza

Bernardini

et al. 2020

Cancers

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This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Proietti

Skroza

Bernardini

et al. 2020

Cancers

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“…CDKN2A is a tumor suppressor gene and genetic alterations of CDKN2A such as deletions are possible resistance mechanisms in a therapy with BRAF and MEK inhibitors. 24,25 Finally, it should be noted that the sequencing results of tumor tissue revealed, in addition to BRAF, numerous other genes that could also have been monitored. This point is relevant in view of patients whose tumors do not have a BRAF mutation.…”

Section: Discussionmentioning

confidence: 99%

<p>Circulating Tumor DNA Correlates with Outcome in Metastatic Melanoma Treated by BRAF and MEK Inhibitors – Results of a Prospective Biomarker Study</p>

Forschner¹,

Weißgraeber²,

Hadaschik³

et al. 2020

OTT

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Purpose: BRAF and MEK inhibitors significantly improved the prognosis of metastatic melanoma. Nevertheless, initial treatment response may be only temporary. Liquid biopsies (LB) offer a possibility to monitor patients by measuring circulating tumor DNA (ctDNA). We sought to find out whether ctDNA can be used to reliably determine progressive disease under targeted therapy. In addition, we wanted to check whether ctDNA may represent a possible prognostic marker for survival. Patients and Methods: We included 19 melanoma patients with BRAF and MEK inhibitor therapy. For each patient, a 710 gene panel was analyzed on the latest available tumor tissue before the start of therapy. Repetitive LB were collected in which BRAF V600E/K mutations were monitored using digital droplet PCR (ddPCR). We correlated radiological staging results and overall survival with ctDNA results. Results: In 13 patients, ctDNA was detectable when starting targeted therapy, whereas in six patients, ddPCR was always negative, which we confirmed with ultra-deep sequencing. All patients with initially detectable ctDNA had ctDNA values declining to zero during followup, increasing again at the time of extracerebral progression or even slightly before detection by imaging. Survival was significantly worse for patients with elevated LDH (p=0.034) or detectable ctDNA (p=0.008) at the start of targeted therapy. Conclusion: Therapy monitoring by ctDNA seems to be a reliable method for detecting extracranial progression, even more sensitive and specific than LDH or S100B. However, due to the small number of cases in our study, further studies are necessary.

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“…Melanoma is mostly treated with inhibitors of the MAPK signaling pathway that targets BRAF or MEK kinase (137). However, the treatment response rate in the middle and late stages of treatment is not high, which may be due to the reactivation of the MAPK signaling pathway and/or the activation of the PI3K-AKT pathway caused by selected genetic changes before or during treatment, which caused the primary and acquired resistance (138). BRAF600E and Rac1P29S are hot spot mutations in melanoma.…”

Section: Rac1 Is Involved In the Regulation Of Resistance To Tumor Therapymentioning

confidence: 99%

Rac1, A Potential Target for Tumor Therapy

et al. 2021

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RAS-related C3 botulinum toxin substrate 1 (Rac.1) is one of the important members of Rho GTPases. It is well known that Rac1 is a cytoskeleton regulation protein that regulates cell adhesion, morphology, and movement. Rac1 is highly expressed in different types of tumors, which is related to poor prognosis. Studies have shown that Rac1 not only participates in the tumor cell cycle, apoptosis, proliferation, invasion, migration and angiogenesis, but also participates in the regulation of tumor stem cell, thus promoting the occurrence of tumors. Rac1 also plays a key role in anti-tumor therapy and participates in immune escape mediated by the tumor microenvironment. In addition, the good prospects of Rac1 inhibitors in cancer prevention and treatment are exciting. Therefore, Rac1 is considered as a potential target for the prevention and treatment of cancer. The necessity and importance of Rac1 are obvious, but it still needs further study.

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Genetic Profiling of Advanced Melanoma: Candidate Mutations for Predicting Sensitivity and Resistance to Targeted Therapy

Cited by 22 publications

References 47 publications

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

<p>Circulating Tumor DNA Correlates with Outcome in Metastatic Melanoma Treated by BRAF and MEK Inhibitors – Results of a Prospective Biomarker Study</p>

Rac1, A Potential Target for Tumor Therapy

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