A novel PDGFRA mutation in gastrointestinal stromal tumours, L839P, is sensitive to imatinib in vitro

Bai, Chenguang; Liu, Xiaohong; Zheng, Jianming; Qiu, Cen; Zhu, Yan; Xu, Jingjing; Zhao, Jing; Ma, Dalie

doi:10.3892/ol.2012.599

Cited by 3 publications

(2 citation statements)

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“…These mutational events may be better suited for targeted therapy. Given that, there are specific drugs that target BRAF [ 51 – 53 ], PDGFRA [ 54 – 56 ], and ARID1A [ 57 ] mutants, patients harboring these mutations could benefit from these specific treatments.…”

Section: Discussionmentioning

confidence: 99%

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

et al. 2017

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BackgroundSolid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches.MethodsWe isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments.ResultsMutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment.ConclusionsThis study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0468-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

et al. 2017

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“…In addition to previously reported five mutations (V561A, K646E, H816Y, L839P, and Y849C; refs. [27][28][29][30], the other 13 mutations were novel (Table 2). No common mutation was found.…”

Section: Mutation Types Of Pdgfra In Melanomamentioning

confidence: 99%

Large-scale Analysis of PDGFRA Mutations in Melanomas and Evaluation of Their Sensitivity to Tyrosine Kinase Inhibitors Imatinib and Crenolanib

Dai

Kong

et al. 2013

Clinical Cancer Research

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Purpose: Platelet-derived growth factor receptor a (PDGFRA) is a target for tyrosine kinase inhibitor (TKI)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese patients with melanoma and determined the inhibitory potency of TKIs, such as imatinib and crenolanib, on mutant PDGFRA.Experimental Design: Of note, 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14, and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by Western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays.Results: PDGFRA mutations were observed in 4.6% (16 of 351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations seem to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness, and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y, and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib.Conclusions: PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that patients with melanoma harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment.

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High-resolution melting analysis is a sensitive diagnostic tool to detect imatinib-resistant and imatinib-sensitive PDGFRA exon 18 mutations in gastrointestinal stromal tumors

et al. 2014

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A novel PDGFRA mutation in gastrointestinal stromal tumours, L839P, is sensitive to imatinib in vitro

Cited by 3 publications

References 26 publications

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

Large-scale Analysis of PDGFRA Mutations in Melanomas and Evaluation of Their Sensitivity to Tyrosine Kinase Inhibitors Imatinib and Crenolanib

High-resolution melting analysis is a sensitive diagnostic tool to detect imatinib-resistant and imatinib-sensitive PDGFRA exon 18 mutations in gastrointestinal stromal tumors

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