Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform

Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD), the most common histological subtype, accounts for 40% of all cases. While genetically engineered mouse models (GEMMs) recapitulate the histological progression and transcriptional evolution of human LUAD, they are slow and technically demanding. In contrast, cell line transplant models are fast and flexible, but are often derived from clonal idiosyncratic tumors that fail to capture the full spectrum of clinical disease. Organoid technologies provide a means to create next-generation cancer models that integrate the most relevant features of autochthonous and transplant-based systems, yet robust and faithful LUAD organoid platforms are currently lacking. Here, we describe optimized conditions to continuously expand murine alveolar type 2 cells (AT2), a prominent cell-of-origin for LUAD, in organoid culture. These organoids display canonical features of AT2 cells, including marker gene expre..... READ ARTICLE

bioRxiv DOI:10.1101/2021.12.07.471632

Authors: Santiago Naranjo, Christina M. Cabana, Lindsay M. LaFave, Peter M.K. Westcott, Rodrigo Romero, Arkopravo Ghosh, Laura Z. Liao, Jason M. Schenkel, Isabella Del Priore, Arjun Bhutkar, Dian Yang, Tyler Jacks

Pre-Clinical, Pre-Print, group1Kirk SmithDecember 7, 2021Lung adenocarcinoma, organoid culture

Comparative Efficacy of Systemic Agents for Brain Metastases From Non-Small-Cell Lung Cancer With an EGFR Mutation/ALK Rearrangement: A Systematic Review and Network Meta-Analysis

Brain metastases (BM) from non-small-cell lung cancer (NSCLC) are frequent and carry significant morbidity, and current management options include varying local and systemic therapies. Here, we performed a systematic review and network meta-analysis to determine the ideal treatment regimen for NSCLC BMs with targetable EGFR-mutations/ALK-rearrangements.</sec><sec>MethodsWe searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published from inception until June 2020. Comparative RCTs including ≥10 patients were selected. We used a frequentist random-effects model for network meta-analysis (NMA) and assessed the certainty of evidence using the GRADE approach. Our primary outcome of interest was intracranial progression-free survival (iPFS).</sec><sec>ResultsWe included 24 studies representing 19 trials with 1623 total patients. Targeted tyrosine kinase inhibitors (TKIs) significantly improved iPFS, wit..... READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.739765

Authors: Taslimi Shervin, Brar Karanbir, Ellenbogen Yosef, Deng Jiawen, Hou Winston, Moraes Fabio Y., Glantz Michael, Zacharia Brad E., Tan Aaron, Ahluwalia Manmeet S., Khasraw Mustafa, Zadeh Gelareh, Mansouri Alireza

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

Targeted kinase inhibitors improve the prognosis of lung cancer patients with ALK alterations (ALK+). However, due to the emergence of acquired resistance and varied clinical trajectories, early detection of disease progression is warranted to guide patient management and therapy decisions. We utilized 343 longitudinal plasma DNA samples from 43 ALK+ NSCLC patients receiving ALK-directed therapies to determine molecular progression based on matched panel-based targeted next-generation sequencing (tNGS), and shallow whole-genome sequencing (sWGS). ALK-related alterations were detected in 22 out of 43 (51%) patients. Among 343 longitudinal plasma samples analyzed, 174 (51%) were ctDNA-positive. ALK variant and fusion kinetics generally reflected the disease course. Evidence for early molecular progression was observed in 19 patients (44%). Detection of ctDNA at therapy baseline indicated shorter times to progression compared to cases without mutations at baseline. In patients who succumb..... READ ARTICLE

Nature Profolio Journal: Precision Oncology DOI:10.1038/s41698-021-00239-3

Authors: Angeles, A.K., Christopoulos, P., Yuan, Z., Bauer, S., Janke, F., Ogrodnik, S.J., Reck, M., Schlesner, M., Meister, M., Schneider, M.A., Dietz, S., Stenzinger, A., Thomas, M. and Sültmann, H.

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Video, group1Kirk SmithDecember 5, 2021

A new ALK inhibitor overcomes resistance to first- and second-generation inhibitors in NSCLC

More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU-MP-5 as a new-generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU-MP-5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild-type or mutant EML4-ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU-MP-5. In addition, XMU-MP-5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological eff..... READ ARTICLE

EMBO Molecular Medicine
DOI:10.15252/emmm.202114296

Authors: Yue Lu, Zhenzhen Fan, Su-Jie Zhu, Xiaoxing Huang, Zhongji Zhuang, Yunzhan Li, Zhou Deng, Lei Gao, Xuehui Hong, Ting Zhang, Li Li, Xihuan Sun, Wei Huang, Jingfang Zhang, Yan Liu, Baoding Zhang, Jie Jiang, Fu Gui, Zheng Wang, Qiyuan Li, Siyang Song, Xin Huang, Qiao Wu, Lanfen Chen, Dawang Zhou, Jianming Zhang, Cai-Hong Yun, Liang Chen and Xianming Deng

Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report

This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.10.015

Authors: Qi Liang, Huanhuan Xu, Yiqian Liu, Weiming Zhang, Chongqi Sun, Meng Hu, Yizhi Zhu, Shanyue Tan, Xian Xu, Sumeng Wang and Lingxiang Liu

Pharmacovigilance Analysis of Cardiac Toxicities Associated With Targeted Therapies for Metastatic NSCLC

Targeted therapies have transformed treatment of driver-mutated metastatic NSCLC. We compared cardiovascular adverse events between and within targeted therapy classes. READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2021.07.030

Authors: Sarah Waliany, Han Zhu, Heather Wakelee, Sukhmani K. Padda, Millie Das, Kavitha Ramchandran, Nathaniel J. Myall, Thomas Chen, MD, Ronald M. Witteles, Joel W. Neal

Review Paper, group1Kirk SmithDecember 1, 2021NSCLC, Targeted therapies, Arrhythmia, Heart failure, Cardio-oncology

Inhibition of c-Jun N-terminal kinase signaling increased apoptosis and prevented the emergence of ALK-TKI-tolerant cells in ALK-rearranged non-small cell lung cancer

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs—alectinib and brigatinib—in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly d..... READ ARTICLE

Cancer Letters DOI:10.1016/j.canlet.2021.09.018

Authors: Keiko Tanimura, Tadaaki Yamada, Mano Horinaka, Yuki Katayama, Sarina Fukui, Kenji Morimoto, Takayuki Nakano, Shinsaku Tokuda, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino, Kazue Yoneda, SeijiYano, ToshiyukiSakai and KoichiTakayama