Discovery of <i>ALK</i>‐<i>PTPN3</i> gene fusion from human non‐small cell lung carcinoma cell line using next generation RNA sequencing

Kim, Pora; Jung, Yeonjoo; Keum, Juhee; Kim, Soon Nam; Choi, Yong Soo; Gu, In; Lee, Jinseon; Choi, So Jung; Kim, Sujin; Lee, Jong Eun; Kim, Young Tae; Lee, Sanghyuk; Kim, Jaesang

doi:10.1002/gcc.21945

Cited by 78 publications

(50 citation statements)

References 14 publications

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“…The key net result appears to be the null mutation of one allele of PTPN3, a gene with tumor suppressor activity. Consistently, ectopic expression of PTPN3 in NSCLC cell lines led to inhibition of colony formation (Jung et al, 2012).…”

Section: Discussionmentioning

confidence: 56%

“…Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Jung et al (2012) applied the next-generation sequencing technique to analyze the transcriptome of the non-small cell lung carcinoma (NSCLC) cell line H2228, and discovered a fusion transcript composed of multiple exons of anaplastic lymphoma receptor tyrosine kinase (ALK) and PTPN3. Detailed analysis of the genomic structure revealed that a portion of the genomic region encompassing exons 10 and 11 of ALK has been translocated into the intronic region between exons 2 and 3 of PTPN3.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Comparative analyses of histone H3K9 trimethylations in the heart and spleen of normal humans

Sui¹,

Cao²,

Che³

et al. 2014

Genet. Mol. Res.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Comparative analyses of histone H3K9 trimethylations in the heart and spleen of normal humans

Sui¹,

Cao²,

Che³

et al. 2014

Genet. Mol. Res.

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“…Variants v1, v2, v3a and v3b of EML4-ALK fusion gene are the most commonly detected, together accounting for more than 90% of variants in some series (20). Although more uncommon, other ALK fusion partners have been identified as TFG (TRK-fused gene), KIF5B, PTPN3 and KLC1 (21)(22)(23). The different EML4 variants and the further partner genes do not seem to significantly impact on biology and sensitivity of ALK-rearranged malignant cells and tumors to specific inhibitors (24-26) although a putative role in conditioning response to treatments has been reported in vitro (27).…”

Section: Molecular Pathology Of Alk-rearranged Nsclcmentioning

confidence: 99%

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti¹,

Tiseo²,

Maïo³

et al. 2016

Transl. Lung Cancer Res.

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Abstract:Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/ RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

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“…Also Ou et al recently reported that the emergence of ALK -resistant mutations occurred more commonly in patients with variant 3 EML4-ALK rearrangement than in patients with variant 1 tumors [4]. Other rarer ALK fusions occur such as KIF5B-ALK [5], KLC1-ALK [6], and ALK-PTPN3 [7], but they collectively are less frequent than the ALK-EML4 rearrangement [8], and therefore little is known about their clinical significance with respects to different response to ALK TKIs. In general, patients with ALK -rearranged NSCLC tend to be younger, never smokers, and have lung adenocarcinoma, though rarely patients with other lung cancer histologies have also been found to harbor this mutation [9].…”

Section: Introductionmentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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Discovery of ALK‐PTPN3 gene fusion from human non‐small cell lung carcinoma cell line using next generation RNA sequencing

Cited by 78 publications

References 14 publications

Comparative analyses of histone H3K9 trimethylations in the heart and spleen of normal humans

Comparative analyses of histone H3K9 trimethylations in the heart and spleen of normal humans

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

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