RON tyrosine kinase mutations in brain metastases from lung cancer.
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ABSTRACT:
SUBMITTER: Milan M
PROVIDER: S-EPMC5838354 | biostudies-literature | 2018 Jan
REPOSITORIES: biostudies-literature
Publications
RON tyrosine kinase mutations in brain metastases from lung cancer.
Milan Melissa M Benvenuti Silvia S Balderacchi Alice Maria AM Virzì Anna Rita AR Gentile Alessandra A Senetta Rebecca R Cassoni Paola P Comoglio Paolo Maria PM Stella Giulia Maria GM
ERJ open research 20180101 1
<b><i>RON</i> mutations might identify actionable targets in highly aggressive lung tumours</b> http://ow.ly/RTUp30hSBX6. ...[more]
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Project description:ObjectivesThe purpose of this study was to examine the impact of epidermal growth factor receptor (EGFR) mutation status and tyrosine kinase inhibitors (TKIs) on the survival of brain metastases (BM) in patients with surgically resected non-small cell lung cancer (NSCLC).MethodsWe selected the patients who had developed metastatic NSCLC; analyzed the differences between brain metastases and other sites of metastases, including patient characteristics, EGFR status, and survival; and selected the patients who had BM for further investigation. We also compared the treatment effects of first-generation TKIs with those of second-/third-generation TKIs.ResultsA total of 785 cases of stage I-IIIa NSCLC were reviewed. Thirty-six (4.6%) patients were identified as having BM. Among them, 14 patients had a mutated EGFR status. No association between EGFR mutation and the incidence of BM was observed (p = 0.199). Patients with mutated EGFRs had significantly longer overall survival and post-recurrence survival than patients with wild-type EGFR mutation (p = 0.001 for both). However, there was no survival difference between patients with exon 19 and exon 21 mutations (p = 0.426). Furthermore, patients who received the second- and/or third-generation EGFR-TKIs had better survival than patients who only received first-generation EGFR-TKIs (p = 0.031). A multivariate analysis indicated that the next-generation TKIs (HR, 0.007; 95% CI, 0.000 to 0.556; p = 0.026) and a longer interval before BM development (HR, 0.848; 95% CI, 0.733 to 0.980; p = 0.025) were significant factors in longer survival.ConclusionsEGFR-TKIs were effective in treating NSCLC patients with BM after curative pulmonary surgery, especially in those patients harboring EGFR mutations. Furthermore, the second-/third-generation EGFR-TKIs showed more promising results than the first-generation EGFR-TKIs in treating those particular patients, though larger studies needed to further prove the results.
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Project description:BACKGROUND:Aberrant expression of RON, a MET family receptor tyrosine kinase, has been correlated to tumor growth and metastasis. Intense research efforts are on to target RON using small molecule tyrosine kinase inhibitors or specific antibodies. However, progress towards specific targeting of RON is hampered by a lack of understanding of the nature and number of isoforms of RON expressed by tumors. We hypothesize that formation of different isoforms via alternative splicing may be fundamental to the tumor promoting functions associated with aberrantly expressed RON in cancers. METHODS:In this study, we analyzed the transcript sequence variations caused by alternative splicing in the C-terminal region of RON cDNA by PCR amplification and sequencing of five small cell lung carcinoma (SCLC) and seven non-small cell lung carcinoma (NSCLC) cell lines. RESULTS:Results revealed the presence of two alternatively spliced variants, each caused by unique exon(s) deletion: a previously known transcript variant lacking exon 19 and a novel one lacking exons 18+19. The two alternatively spliced variants together with the wild-type transcript were detected in each of the 12 lung cancer cell lines analyzed. Combined loss of exons 18+19 results in an in-frame deletion of 303 nucleotides corresponding to 101 amino acids of the tyrosine kinase domain. Translation products of transcript variants lacking exons 18 and 19 are expected to dominant negatively inhibit ligand stimulated RON signaling. CONCLUSIONS:The ubiquitous presence of alternatively spliced transcripts and their translation products may affect quantitative expression analysis, either by immunological or PCR methods, by interfering with estimation of normal RON, leading to exaggerated values. Besides, RON isoforms with dominant negative activities may interfere with siRNA based functional analysis of wild-type RON.
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Project description:BackgroundChemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are controversial in the treatment of patients with brain metastases from non-small-cell lung cancer (NSCLC).MethodsWe retrospectively studied the effects of solely localized treatment or localized treatment in combination with chemotherapy and/or EGFR tyrosine kinase inhibitors on outcomes in 210 NSCLC patients with brain metastases. The effects of treatment modality, Karnofsky performance status, age, primary tumor histology, number of brain metastases, and other factors on survival time were analyzed, and the robustness of two prognostic indices, ie, recursive partitioning analysis and graded prognostic assessment, was evaluated.ResultsThe median survival time in patients with systemic medication and localized treatments was higher than in those with localized treatments alone (11 versus 3 months, P=0.000). Within the systemic medication group, median survival time was significantly longer for EGFR tyrosine kinase inhibitors than for other types of chemotherapy (12 versus 9 months, P=0.002). In the EGFR tyrosine kinase inhibitor group, median survival time for patients with EGFR gene mutation was 20 months versus 8 months for those with the wild-type EGFR gene. The median survival time with pemetrexed was significantly higher than with other chemotherapies (13 versus 7 months, P=0.006). In multivariate analysis, the prognosis was significantly correlated with treatment modality (P=0.000), Karnofsky performance status (P=0.000), number of brain metastases (P=0.001), and histologic tumor type (P=0.007). In the graded prognostic assessment model, survival curves for the subgroups showed clear separations.ConclusionNSCLC patients with brain metastasis benefited from pemetrexed and/or tyrosine kinase inhibitors along with localized treatments, and the graded prognostic assessment index is a robust model for prognostic evaluation.
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