Forced degradation of Ceritinib under stress conditions: Structural interpretation of novel degradants using HR-MS/MS and NMR

The current work describes the preparative isolation and structural interpretation of acid degradation product of ceritinib (CRB). The drug is exposed to different stress conditions (acid, base hydrolysis, oxidation, thermal and photolytic) as suggested by International Conference on Harmonisation guidelines (ICH). The degradation of drug (CRB) is observed when exposed to acidic condition whereas the drug is stable in remaining stress conditions. The separation between drug and acid degradant was attained on a C18 BEH UPLC column (50 mm × 2.1 mm, 1.7 μm) in a gradient separation mode. The mobile phase comprises of acetonitrile and 0.05% formic acid buffer at a flow rate of 0.6 mL/min and UV wavelength monitored at 215 nm. One novel degradation product formed in acidic condition was isolated by Preparative HPLC (Prep-HPLC). Structural interpretation and characterisation done by HR-MS/MS and NMR studies which is not yet described in the literature. READ ARTICLE

Materials Today: Proceedings DOI:10.1016/j.matpr.2020.01.588.

Authors: Soujanya Vajjha, Vijay Bommuluri, Chidananda Swamy Rumalla, Muralidharan Kaliyaperumal, Raghu Babu Korupolu, Vidyasagar chopella

Pre-ClinicalKirk SmithJuly 12, 2020Ceritinib, Drug degradation, Structural elucidation

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma

Summary: To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification ..... READ ARTICLE

Cell DOI:10.1016/j.cell.2020.06.013

Authors: Michael A. Gillette, Shankha Satpathy, Song, Cao,.. AND MANY MORE

ZX-29, a novel ALK inhibitor, induces apoptosis via ER stress in ALK rearrangement NSCLC cells and overcomes cell resistance caused by an ALK mutation

Although anaplastic lymphoma kinase (ALK) inhibitors have good clinical efficacy, the inevitable development of drug resistance is the most common obstacle to their clinical application. There is an urgent need to develop more effective and selective ALK inhibitors to overcome the problem of drug resistance. Here, we screened a series of ALK inhibitors and found that ZX-29 displayed potent cytotoxic activity against ALK rearrangement non-small cell lung cancer (NSCLC) NCI-H2228 cells. Then, we investigated the antitumor effects of ZX-29. We demonstrated that ZX-29 time- and dose-dependently inhibited the viability of NCI-H2228 cells, induced cell cycle arrest in the G1 phase, and then they subsequently progressed into cell death. The type of cell death induced by ZX-29 was apoptosis through endoplasmic reticulum (ER) stress. Interestingly, ZX-29 induced protective autophagy, and inhibiting autophagy could enhance the antitumor effect of ZX-29. Furthermore, ZX-29 suppressed tumor growth..... READ ARTICLE

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research DOI:10.1016/j.bbamcr.2020.118712

Authors: Wenfeng Gou, Zengqiang Li, Xiaobo Xu, Jiwei Shen, Ming Guo, Xuejiao Zhou, Xiaoning Zhang, Yingliang Wu, Xin Zhai, Daiying Zuo

Pre-ClinicalKirk SmithJuly 1, 2020ALK, NSCLC, ER stress, Apoptosis, Drug resistance

A novel EML4-ALK BIRC6-ALK double fusion variant in lung adenocarcinoma confers sensitivity to alectinib

ALK receptor tyrosine kinase gene (ALK) rearrangement is a common driver mutation for patients with NSCLC. At present, more than 20 fusion partners for ALK in NSCLC have been reported. The most common partner of ALK rearrangement is echinoderm microtubule-associated protein-like 4 gene (EML4). But ALK double fusion is rare. ALK inhibitors are widely used in cancer-targeted therapy now. The progression-free survival of patients with ALK-positive NSCLC treated with alectinib as a first-line treatment is varied due to different fusion forms of ALK [ [1] ]. Therefore, it is of great clinical significance to continuously explore new forms of ALK fusion and study its correlation with drug sensitivity. With the development of next-generation sequencing (NGS) technology, ALK detection is becoming more and more precise, Herein we described a patient with advanced lung adenocarcinoma who presented simultaneously with two novel fusions, EML4-ALK and BIRC6-ALK, and with sensitivity to alectinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.030

Authors: Jiang-Ming Zhong, Gui-Feng Zhang, Li Lin, De-Yu Li, Zhen-Hua Liu

Is Retention of the 5′ Nononcogenic ALK Fusion Variant a Novel Poor Prognostic Factor in ALK-Positive NSCLC?

... A simple question that has remained unanswered since the discovery of the EML4-ALK fusion in 2007 is “what happens to the 5′ ALK DNA chromosomal fragment that contains ALK exons 1-19?” Routine clinical use of NGS in NSCLC allows the detection of the presence of reciprocal or nonreciprocal translocations in a subset of cases, which could not be identified using FISH or IHC platforms... Patients with ALK+ NSCLC with brain metastases but did not retain the 5′ ALK fragment had similar poor outcomes when treated with crizotinib.21 Last, whether the shorter PFS from crizotinib treatment can be translated to next-generation ALK tyrosine kinase inhibitors is also unknown. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.04.031

Authors: Susan J. Hsiao, Sai-Hong Ignatius Ou

Intergenic Breakpoints Identified by DNA Sequencing Confound Targetable Kinase Fusion Detection in NSCLC

Introduction: Next-generation sequencing (NGS) based on genomic DNA has been widely applied for gene rearrangement detection in patients with NSCLC. However, intergenic-breakpoint fusions, in which one or both genomic breakpoints localize to intergenic regions, confound kinase fusion detection. We evaluated the function of intergenic-breakpoint fusions with multiplex molecular testing approaches... Conclusions: Intergenic-breakpoint fusions detected by DNA sequencing confound kinase fusion detection in NSCLC, as functional fusion transcripts may be generated or not. Additional validation testing using RNA/protein assay should be performed in intergenic-breakpoint fusion cases to guide optimal treatment. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.02.023

Authors: Weihua Li, Yutao Liu, Wenbin Li, Li Chen, Jianming Ying

A User’s Guide to Lorlatinib

Rearrangements of the ALK gene are found in approximately 5% of non-small-cell lung cancer. It is of particular importance to test for this rearrangement in patients with metastatic lung adenocarcinoma because these tumors are highly sensitive to therapy with ALK-targeted inhibitors.

Lorlatinib is a reversible potent third generation tyrosine kinase inhibitor that is highly selective and targets ALK and ROS1. It was developed to target resistant ALK mutants including the most common G1202R. Lorlatinib has excellent central nervous system (CNS) penetration and its efficacy has also been demonstrated even in patients with intracranial metastases after progression on second generation ALK inhibitors. Potential toxicities include neurocognitive effects and hyperlipidemia.

“A User’s Guide to Lorlatinib” reviews the mechanism of action, pharmacology and clinical trial data. Also covering the management of adverse events, this “guide” has been prepared to be a practical reference tool to both clinicians and basic researchers. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.102969

Authors: Misako Nagasaka, Yubin Ge, Ammar Sukari, Geetika Kukreja, Sai-Hong IgnatiusOu

Chapter 13 - Gastrointestinal Toxicities of Targeted Therapy

Although targeted therapies are generally better tolerated than standard chemotherapy, there are some gastrointestinal side effects that should be kept in consideration. Most side effects are mild to moderate in severity, but some can be life threatening. Diarrhea is the most common side effects of tyrosine kinase inhibitors (TKIs). The majority of the cases can be managed with prophylactic and rescue use of anti-diarrhea medications. Aplastic lymphoma kinase (ALK) inhibitors, mesenchymal epithelial transition factor(c-MET) and poly ADP-ribose polymerase (PARP) inhibitors are known to cause nausea and vomiting. Most cases of nausea and vomiting can be managed by medications such as serotonin antagonists, NK-1 antagonists, dopamine antagonists or anti-anxiety medications. Prior to prescribing c-KIT TKIs (sunitinib, regorafenib), multi-TKIs (pazopanib), MEK inhibitors (trametinib), anti-HER-2 therapy (lapatinib) and anti-EGFR targeting agents (gefitinib, erlotinib), baseline liver function tests should be performed and then monitored periodically to prevent liver damage. READ ARTICLE

Handbook of Cancer Treatment-Related Symptoms and Toxicities DOI:10.1016/B978-0-323-67241-2.00013-6

Authors: Tahmida Chowdhury, Ammar Sukari, Misako Nagasaka

Continual Improvement of the Reliability of EML4-ALK Rearrangement Detection in Non–Small-Cell Lung Cancer: A Long-Term Comparison of ALK Detection in China

The results of EML4-ALK testing are critical to manage ALK tyrosine kinase receptor inhibitor treatment. Thus, the accurate detection of ALK rearrangement is increasingly becoming a matter of serious concern. To address this issue, a long-term EML4-ALK proficiency testing (PT) scheme was launched in China in 2015, serving as an educational tool for assessing and improving the testing quality of EML4-ALK fusion detection. Responses across 20 different PT samples interrogating three different variants and wild-type samples were collected between 2015 and 2019. Performance was analyzed by evaluating the detection methods, kits, and pre-analytic practices used to further display the landscape of changing conditions of the reliability of EML4-ALK testing... Throughout this 5-year EML4-ALK rearrangement detection PT scheme, a large amount of valuable historical data was collected. As it is of interest to investigate whether the performance of EML4-ALK rearrangement tests has changed over th..... READ ARTICLE

The Journal of Molecular Diagnostics DOI:10.1016/j.jmoldx.2020.03.007

Authors: Rongxue Peng, Rui Zhang, Jiawei Zhang, Ping Tan, Yanxi Han, Kuo Zhang, Guigao Lin, Jiehong Xie, Jinming Li

Acquired multiple mutations ALK I1171N, L1196M and G1202R mediate lorlatinib resistance in EML4-ALK-rearranged malignant pleural mesothelioma: a case report

EML4-ALK rearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient with EML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence of ALK I1171N and L1196M at alectinib progression. Meanwhile, ALK I1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be in cis to G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both a..... READ ARTICLE

Therapeutic Advances in Respiratory Disease DOI:10.1177/1753466620935770

Authors: Jia Hu, Baoshi Zhang, Fangfang Yao, Yan Fu, Dianjun Chen, Donghui Li, Nan Du, Analyn Lizaso, Jinlei Song, Lu Zhang, Xiaosong Li

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Even though ALK inhibitors in the clinic lead to excellent initial responses, acquired resistance to these inhibitors due to on-target mutations or parallel pathway alterations is a major clinical challenge. Exploring these mechanisms of resistance, we found that EML4-ALK cells parental or resistant to crizotinib, ceritinib or alectinib are remarkably sensitive to inhibition of CDK7/12 with THZ1 and CDK9 with alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. Importantly, alvocidib reduced tumour progression in xenograft mouse models. In summary, our study takes advantage of the transcriptional addiction hypothesis to propose a new treatment strategy for a subset of patients with acquired resistance to first-, second- and third-generation ALK inhibitors. READ ARTICLE

EMBO Molecular Medicine DOI:10.15252/emmm.201911099

Authors: Athanasios R Paliouras, Marta Buzzetti, Lei Shi, Ian J Donaldson, Peter Magee, Sudhakar Sahoo, Hui-Sun Leong, Matteo Fassan, Matthew Carter, Gianpiero Di Leva, Matthew G Krebs, Fiona Blackhall, Christine M Lovly, Michela Garofalo

Pre-ClinicalKirk SmithJune 17, 2020ALK/EML4 translocation, ALKi, CDKi, NSCLC, drug resistance

A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors

Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity. READ ARTICLE

Frontiers in Pharmacology DOI:10.3389/fphar.2020.00891

Authors: Ying Jin, Zhifei Xu, Hao Yan, Qiaojun He, Xiaochun Yang, and Peihua Luo

Recurrent hyperglycemic hyperosmolar state after re-administration of dose-reduced ceritinib, an anaplastic lymphoma kinase inhibitor

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor with clinical activity in crizotinib-resistant ALK-positive non-small cell lung cancer and in treatment-naïve ALK-positive disease. Hyperglycemia is a known adverse event, but the mechanism by which ceritinib causes hyperglycemia is unknown, and whether ceritinib causes hyperglycemic emergencies is unclear. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) recurrence after the re-administration of dose-reduced ceritinib. A 78-year-old man with type 2 diabetes diagnosed as having advanced lung adenocarcinoma had been treated with alogliptin (25 mg/day) for the diabetes and with ceritinib for the lung cancer. After 28 days of ceritinib administration, he was admitted to our hospital due to HHS. His blood glucose level improved with insulin therapy after discontinuation of the ceritinib. He then received re-administration with a decreased ceritinib dose while maintaining the insul..... READ ARTICLE

Diabetology International DOI:10.1007/s13340-020-00442-w

Authors: Miyoshi, Y., Ogawa, O., Nishida, A. et al.

Real world experience of treatment and outcome in ALK-rearranged metastatic nonsmall cell lung cancer: A multicenter study from India

Background: Anaplastic lymphoma kinase (ALK) rearranged metastatic non-small cell lung cancer (NSCLC) comprises 5%-7% of all lung cancer and carries a good prognosis with available ALK-inhibitors. Majority of registration trials in ALK-inhibitors did not include Indian patients. Hence, this study was planned to analyze the outcome of Indian patients treated with ALK-inhibitors and associated challenges. Results: A total of 274 patients were studied, out of which 250 patients received ALK inhibitor and were analyzed further for outcome. The median age was 50 years (range: 24-82) and male to female ratio of 1.17:1. ALK was evaluated by immunohistochemistry in majority of patients (97%), 3 patients by FISH and 3 more patients were evaluated by both methods. Sixty-five percent (n = 162) of the patients received ALK-inhibitor as first line therapy, 51 patients received ALK-inhibitor as switch maintenance therapy after initial chemotherapy. Crizotinib and Ceritinib were used in 88% and 12%,..... READ ARTICLE

Cancer DOI:10.1016/j.currproblcancer.2020.100571.

Authors: Amol Patel, Ullas Batra, Kuruswamy Thurai Prasad, Deepak Dabkara, Joydeep Ghosh, Manasi Sharma, Navneet Singh, P. Suresh, Parveen Jain, Prabhat Singh Malik, Priyanshu Choudhary, Sandip Ganguly, Sachin Khurana, Shivashankara MS, Sneha Bothra, Valliappan Muthu, Bivas Biswas,

MET Alterations Are a Recurring and Actionable Resistance Mechanism in ALK-Positive Lung Cancer

MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET. READ ARTICLE

Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-19-3906

Authors: Ibiayi Dagogo-Jack, Satoshi Yoda, Jochen K. Lennerz, Adam Langenbucher, Jessica J. Lin, Marguerite M. Rooney, Kylie Prutisto-Chang, Audris Oh, Nathaniel A. Adams, Beow Y. Yeap, Emily Chin, Andrew Do, Hetal D. Marble, Sara E. Stevens, Subba R. Digumarthy, Ashish Saxena, Rebecca J. Nagy, Cyril H. Benes, Christopher G. Azzoli, Michael S. Lawrence, Justin F. Gainor, Alice T. Shaw, Aaron N. Hata

Pre-ClinicalKirk SmithJune 1, 2020MET, ALK+ lung cancer

Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

More than 10 EML4-ALK variants based on the exon breakpoints in EML4 have been identified. Unlike other receptor tyrosine kinase fusion positive NSCLC such as ROS1 or RET fusion, EML4-ALK is the dominant fusion variant in ALK+ NSCLC accounting for approximately 85 % of all fusion variants in ALK+ NSCLC. Currently, eight EML4-ALK variants are generally recognized with a number (1, 2, 3a/b, 4′, 5a/b, 5′, 7, 8) with EML4-ALK variants 1 and 3 being the two most common variants accounting for 75–80 % of the total EML4-ALK variants. Preclinical, retrospective analyses of institutional databases, and global randomized phase 3 trials have demonstrated differential clinical response (overall response rate, progression-free survival) to ALK tyrosine kinase inhibitors (TKIs) between the “short” (v3 and v5) and “long” (v1, v2, v5′, v7, and v8) EML4-ALK variants. We discuss in more details how EML4-ALK variant structure influences protein stability and response to ALK TKIs. Additionally, the most recalcitrant single solvent-front mutation ALK G1202R is more prone to develop among EML4-ALK v3 following sequential use of next-generation ALK TKIs. Furthermore, TP53 mutations being the most common genomic co-alterations in ALK+ NSCLC also contribute to the heterogeneous response to ALK TKIs. Recognizing ALK+ NSCLC is not one homogeneous disease entity but comprised of different ALK fusion variants with different underlying genomic alterations in particular TP53 mutations that modulate treatment response will provide insight into the further optimization of treatment of ALK+ NSCLC patients potentially leading to improvement in survival. READ ARTICLE

Lung cancer DOI: 10.1016/j.lungcan.2021.06.012

Authors: Shannon S. Zhang, Misako Nagasaka, Viola W. Zhu, Sai-Hong Ignatius Ou

Optimizing Mutation and Fusion Detection in NSCLC by Sequential DNA and RNA Sequencing

Introduction: Frequently, patients with locally advanced or metastatic NSCLC are screened for mutations and fusions. In most laboratories, molecular workup includes a multitude of tests: immunohistochemistry (ALK, ROS1, and programmed death-ligand 1 testing), DNA sequencing, in situ hybridization for fusion, and amplification detection. With the fast-emerging new drugs targeting specific fusions and exon-skipping events, this procedure harbors a growing risk of tissue exhaustion... Conclusions: We conclude that sequentially combining DNA NGS and RNA NGS is the most efficient strategy for mutation and fusion detection in smoking-associated NSCLC, whereas for never smokers we recommend a parallel approach. This approach was shown to be feasible on small tissue samples including for cytology tests, can drastically reduce the complexity and cost of molecular workup, and also provides flexibility in the constantly evolving landscape of actionable targets in NSCLC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.01.019

Authors: Danielle Cohen, Liesbeth M. Hondelink, Nienke Solleveld-Westerink, Sandra M. Uljee, Dina Ruano, Anne-Marie Cleton-Jansen, Jan H. von der Thüsen, S. Rajen S. Ramai, Pieter E. Postmus, Jacob F. Graadt van Roggen, Bart P. C. Hoppe, Pieter C. Clahsen, Klaartje W. Maas, Els J. M. Ahsmann, Alexandraten Heuvel, Frank Smedts, Ronald N. van Rossem,Tomvan Wezel

Detection of Nonreciprocal/Reciprocal ALK Translocation as Poor Predictive Marker in Patients With First-Line Crizotinib-Treated ALK-Rearranged NSCLC

Introduction: During nonreciprocal/reciprocal translocation process, 5′-anaplastic lymphoma kinase (ALK) sometimes gets retained in the genome and is detectable by next-generation sequencing; however, no study has investigated its clinical significance. Our study aimed to assess the impact of harboring 5′-ALK on the efficacy of crizotinib. Conclusions: Presence of nonreciprocal/reciprocal ALK translocation was predictive for worse PFS and greater likelihood of baseline brain metastases in patients with ALK-rearranged NSCLC who received first-line crizotinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.02.007

Authors: Yongchang Zhang, Liang Zeng, Chunhua Zhou, Yizhi Li, Lin Wu, Chen Xia, Wenjuan Jiang, Yijuan Hu, Dehua Liao, Lili Xiao, Li Liu, Haiyan Yang, Yi Xiong, Rui Guan, Analyn Lizaso, Aaron S. Mansfield, Nong Yang

Acquired resistance to targeted therapies in NSCLC: Updates and evolving insights

While significant advancements have been made in the available therapies for metastatic non-small cell lung cancer (NSCLC), acquired resistance remains a major barrier to treatment. We have not yet achieved the ability to cure advanced NSCLC with systemic therapy, despite our growing understanding of many of the oncogenic drivers of this disease. Rather, the emergence of drug-tolerant and drug-resistant cells remains the rule, even in the face of increasingly potent targeted therapies. In this review, we provide a broad overview of the mechanisms of resistance to targeted therapy that have been demonstrated across molecular subtypes of NSCLC, highlighting the dynamic interplay between driver oncogene, bypass signaling pathways, shifting cellular phenotypes, and surrounding tumor microenvironment. READ ARTICLE

Pharmacology & Therapeutics DOI:10.1016/j.pharmthera.2020.107522

Authors: Catherine B. Meador, Aaron N. Hata

Epithelioid fibrous histiocytoma of the vulva: Report of a case with next-generation sequencing analysis

Epithelioid fibrous histiocytoma (EFH), also known as epithelioid cell histiocytoma (ECH), is an uncommon benign cutaneous mesenchymal neoplasm that typically occurs in the limbs and consistently harbors ALK gene rearrangements. In this study, we report a unique case of EFH that arose in the labia majora, an unusual site which has been rarely described. The tumor occurred in a 41-year-old woman who presented with a slowly growing painless nodule in the vulva. Histological examination revealed a circumscribed lesion located within the dermis, which was composed of sheets or nests of large polygonal epithelioid cells with abundant eosinophilic cytoplasm. Nuclear atypia was minimal and mitotic figures were rare. Immunohistochemically, the neoplastic cells showed diffuse cytoplasmic staining of ALK protein. Subsequent fluorescence in situ hybridization (FISH) assessment demonstrated a balanced rearrangement of ALK gene. Further next-generation sequencing (NGS) analysis identified SQSTM1-AL..... READ ARTICLE

Human Pathology: Case Reports DOI:10.1016/j.ehpc.2020.200378

Authors: Lu Zhao, Jiahan Liu, Meng Sun, I. Weng Lao, Lin Yu, Jian Wang