scholarly journals Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 620 ◽  
Author(s):  
Connor O’Leary ◽  
Wen Xu ◽  
Nick Pavlakis ◽  
Derek Richard ◽  
Ken O’Byrne
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Response Rates ◽  
Small Cell ◽  
Small Cell Lung ◽  
Asian Ethnicity

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1–2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18–47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.

scholarly journals Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Marianne Oulhen ◽  
Patrycja Pawlikowska ◽  
Tala Tayoun ◽  
Marianna Garonzi ◽  
Genny Buson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

scholarly journals Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

2020 ◽  
Vol 16 (21) ◽  
pp. 1537-1547
Author(s):  
Fumio Imamura ◽  
Madoka Kimura ◽  
Yukihiro Yano ◽  
Masahide Mori ◽  
Hidekazu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

Targeting HER2 Alterations in Non–Small-Cell Lung Cancer: A Comprehensive Review

2020 ◽  
pp. 411-425 ◽  
Author(s):  
Jing Zhao ◽  
Yang Xia
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Antitumor Agents ◽  
De Novo ◽  
Point Mutations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Exon 20

PURPOSE HER2 is a critical gene that drives various solid tumors in addition to those of breast cancer. For example, HER2 plays a role in non–small-cell lung cancer (NSCLC). Overexpression, amplification, and point mutations in HER2 have been described in patients with NSCLC; however, the potential roles of these alterations remain unclear. METHODS We summarize the evidence regarding the distinct impacts of different HER2 aberrations on antitumor agents. Also, we update the therapeutic efficacy of HER2-targeted agents, including anti-HER2 antibodies, antibody-drug conjugates, and small-molecule tyrosine kinase inhibitors, tested in HER2-aberrant NSCLC. RESULTS Although these drugs are not yet standard treatments, certain patients may benefit from these therapies. In this review, we aim to provide an improved understanding of HER2 aberrations in NSCLC, including NSCLC biology and the impacts of each aberration on prognosis and standard treatment. We also highlight the potential of novel anti-HER2 therapies approved by regulatory bodies and those in clinical development. CONCLUSION Compared with HER2 amplification or overexpression, HER2 mutations, especially HER2 exon 20 mutations, are emerging as the most clear targetable driver for HER2-directed therapies in lung cancer. De novo and inducible HER2 pathway activation need to be differentially managed. Further investigations with new strategies are needed.

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