ALK rearrangements in infantile fibrosarcoma-like spindle cell tumors of soft tissue and kidney

Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated “NTRK-rearranged” spindle cell neoplasms. These two groups of tumors demonstrate overlapping morphologies and harbor alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1, and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of pediatric tumors with clinicopathologic features not typical for inflammatory myofibroblastic tumor, but rather with similarities to cCMN/IFS harboring ALK fusions.
Clinicopathologic features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumors occurred in patients from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumors arose in soft tissues and 2 in the kidney. Morphologi..... READ ARTICLE

Histopathology DOI:10.1111/his.14603

Authors: Serena Y. Tan, Alyaa Al-Ibraheemi, William A. Arhens, Javier E. Oesterheld, Julie C. Fanburg-Smith, Yajuan J. Liu, Sheri L. Spunt, Erin R. Rudzinski, Cheryl Coffin, Jessica L. Davis

Clinical utility of next-generation sequencing-based ctDNA testing for common and novel ALK fusions

Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%–99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%–74%) were concordant with p..... READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2021.06.018

Authors: Sebastian Mondaca, Emily S. Lebow, Azadeh Namakydoust, Pedram Razav, Jorge S. Reis-Filho, Ronglai Shen, Michael Offin, Hai-Yan Tu, Yonina Murciano-Goroff, Chongrui Xu, Alex Makhnin, Andres Martinez, Nick Pavlakis, Stephen Clarke, Malinda Itchins, Adrian Lee, Andreas Rimner, Daniel Gomez and Bob T. Li

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superi..... READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2021.07.035

Authors: D. Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James C.H. Yang, Ji-Youn Han, Maximilian J. Hochmair, Ki Hyeong Lee, Angelo Delmonte, Maria Rosario, Garcia Campelo, Dong-Wan Kim, Frank Griesinger, Enriqueta Felip, Raffaele Califano, Alexander I. Spira, Scott N. Gettinger, Marcello Tiseo, Huamao M. Lin, Yuyin Liu, Florin Vranceanu, Huifeng Niu, Pingkuan Zhang and Sanjay Popat

Safety issues with the ALK inhibitors in the treatment of NSCLC: A systematic review

Tyrosine Kinase inhibitors (TKIs) are known to have peculiar toxicity profile, hence, increasing awareness to the safety profile of ALK inhibitors is essential.
A comprehensive systematic review of literature has been conducted to include prospective trials that used the ALK inhibitors Crizotinib, Ceritinib, Alectinib, Brigatinib and Lorlatinib in patients with advanced NSCLC and have available efficacy and toxicity results.
Most of adverse effects of ALKi can be managed efficiently via dose modifications or interruptions. Timely identification of each ALKi pattern of toxicity can prevent treatment-related morbidity and mortality in this palliative setting. READ ARTICLE

Critical Reviews in Oncology/Hematology
DOI:10.1016/j.critrevonc.2018.11.004

Authors: Loay Kassem, Kyrillus S. Shohdy, Shaimaa Lasheen, Omar Abdel-Rahman, Ahmad Ali and Raafat R.Abdel-Malek

Review Paper, group2Kirk SmithNovember 29, 2021ALK inhibitors, Non-small cell lung cancer, Adverse effects

Dramatic response to alectinib in a lung cancer patient with a novel VKORC1L1-ALK fusion and an acquired ALK T1151K mutation

ALK-rearranged lung cancer defines a distinctive molecular cohort of patients whose
outcomes are significantly improved by the availability of ALK inhibitors. Thus, it is imperative
for clinicians to screen appropriate patients for this driver mutation with a molecular testing
platform capable of capturing all ALK fusions. Here, we report a novel VKORC1L1-ALK fusion
and an ALK T1151K resistance mutation detected in a lung cancer patient who had been on
crizotinib for over 8 years. Alectinib induced a dramatic response in this patient demonstrating
its clinical activity against T1151K. This case illustrates the importance of performing repeat
biopsy to explore mechanism(s) of resistance when patients experience disease progression
on an ALK inhibitor. The approach has a direct therapeutic impact particularly when an ALK
resistance mutation is identified. READ ARTICLE

Lung Cancer: Targets and Therapy
DOI:10.2147/LCTT.S186804

Authors: Viola W Zhu, Alexa B Schrock, Thangavijayan Bosemani, Bryan S Benn, Siraj M Ali, and Sai-Hong Ignatius Ou

Case Study, group2Kirk SmithNovember 29, 2021VKORC1L1, T1151, fusion, resistance, crizotinib, lorlatinib

The Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non–small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted condit..... READ ARTICLE

Clinical Pharmacology in Drug Development
DOI:10.1002/cpdd.641

Authors: Meera Tugnait,Neeraj Gupta,Michael J. Hanley,Karthik Venkatakrishnan,Daryl Sonnichsen,David Kerstein,David J. Dorer,Narayana Narasimhan

Identification of a High-Level MET Amplification in CTCs and cfTNA of an ALK-Positive NSCLC Patient Developing Evasive Resistance to Crizotinib

We report the case of a 47-year-old female patient with stage IV NSCLC harboring an echinoderm microtubule associated protein like 4 (EML4)-ALK E20;A20 fusion who was initially treated with four cycles of platinum/pemetrexed until progressive disease. Thereafter, she was treated with crizotinib for 9 months until development of evasive resistance. Subsequently, the patient was primarily resistant to alectinib and ceritinib.
We obtained low-pass copy number profiles of single isolated CTCs after the patient had experienced development of evasive resistance to crizotinib and shown primary resistance to alectinib. Furthermore, we generated additional copy number profiles of CTCs upon development of primary resistance to ceritinib. These analyses revealed the presence of an approximately eightfold MNNG HOS Transforming gene (MET) amplification in all evaluable CTCs at both time points. MET amplification (∼sevenfold) could also be detected in the cfTNA at comparable time points.
This study ..... READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2018.08.2025

Authors: Lars-Arne Berger, Melanie Janning, Janna-Lisa Velthaus, Isabel Ben-Batalla, Stefanie Schatz, Markus Falk, Peter Iglauer, Ronald Simon, Ru Cao, Claudio Forcato, Nicolò Manaresi, Kelli Bramlett, Genny Buson, Annkathrin Hanssen, Markus Tiemann, Guido Sauter, Carsten Bokemeyer, Sabine Riethdorf, Martin Reck, Klaus Pantel, Harriet Wikman, and Sonja Loges

Case Study, group2Kirk SmithNovember 29, 2021Crizotinib, Resistance, MET amplification

Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials

Background
Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC.

Methods
We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases.

Results
A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg an..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-021-08977-0

Authors: Ma HC, Liu YH, Ding KL, Liu YF, Zhao WJ, Zhu YJ, Chang XS, Chen YD, Xiao ZZ, Yu YY, Zhou R, Zhang HB.

Review Paper, group2Kirk SmithNovember 25, 2021ALK, NSCLC, First-line treatment, clinical trial meta-analysis

Structural basis for ligand reception by anaplastic lymphoma kinase

The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity2. Aberrant ALK signalling causes numerous cancers3. In particular, full-length ALK is an important driver in paediatric neuroblastoma4,5, in which it is either mutated6 or activated by ligand7. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides8,9. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of o..... READ ARTICLE

Nature DOI:10.1038/s41586-021-04141-7

Authors: Tongqing Li, Steven E. Stayrook, Yuko Tsutsui, Jianan Zhang, Yueyue Wang, Hengyi Li, Andrew Proffitt, Stefan G. Krimmer, Mansoor Ahmed, Olivia Belliveau, Ian X. Walker, Krishna C. Mudumbi, Yoshihisa Suzuki, Irit Lax, Diego Alvarado, Mark A. Lemmon, Joseph Schlessinger & Daryl E. Klein

Pre-Clinical, group2Kirk SmithNovember 24, 2021Antibody therapy, CNS cancer, Kinases, X-ray crystallography

Prognostic Markers of Survival among Japanese Patients with Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer Receiving First-Line Alectinib.

The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Mean-while, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associat..... READ ARTICLE

Diagnostics DOI:10.3390/diagnostics11122170

Authors: Takeda T, Yamada T, Tanimura K, Nakano T, Ishida M, Tachibana Y, Shiotsu S, Horiuchi S, Hibino M, Okada A, Chihara Y, Takayama K.

ALKtALK with Dr Schurgin: Coping Through the Holidays

Battling cancer and simultaneously celebrating the holidays can be tricky waters to navigate. While feeling grateful to continue traditions with family and friends many also experience being overwhelmed, anxious or depressed. This ALKtALK not only validates these feelings, but provides coping skills to help survive and thrive during this upcoming holiday season. WATCH VIDEO

ALK Positive Inc.

AUTHOR: Dr. Schurgin

Video, group2Kirk SmithNovember 23, 2021

The impact of the ALK fusion variant on clinical outcomes in EML4-ALK patients with NSCLC: a systematic review and meta-analysis

Background: Recent studies showed that ALK-fusion variants are associated with heterogeneous clinical outcomes. However, contradictory conclusions have been drawn in other studies showing no correlation between ALK variants and prognoses. Methods: A systematic review and meta-analysis was performed to evaluate the prognostic value of EML4-ALK fusion variants for patient outcomes. Results: 28 studies were included in the analysis. According to the pooled results, patients harboring variant 1 showed equivalent progression-free survival (PFS) and overall survival (OS) with non-v1 patients (hazard ratio [HR] for PFS: 0.91 [0.68–1.21]; p = 0.499; OS: 1.12 [0.73–1.72]; p = 0.610). Similarly, patients with v3 showed the same disease progress as non-v3 patients (pooled HR for PFS = 1.07 [0.72–1.58]; p = 0.741). However, pooled results for OS suggested that patients with v3 had worse survival than non-v3 patients (HR = 3.44 [1.42–8.35]; p = 0.006). Conclusion: Results suggest that patients with..... READ ARTICLE

Future Oncology DOI:10.2217/fon-2021-0945

Authors: Wang S, Luo R, Shi Y, Han X.

Review Paper, group2Kirk SmithNovember 16, 2021ALK fusion, ALK rearrangement, ALK variant, NSCLC, prognosis

Prevalence and Clinicopathologic Risk Factors for Epidermal Growth Factor Receptor, Anaplastic Lymphoma Kinase, and ROS-1 Fusion in Metastatic Non-small Cell Lung Carcinoma

The purpose of he study was to evaluate the prevalence of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK), and ROS-1 fusions in the patients with metastatic nonsquamous nonsmall cell lung carcinoma (NSCLC) and their relation with different demographic and clinical variables. Methods: A cross-sectional study was carried out on 87 adult patients >18 years of age with a confirmed diagnosis of Stage IV metastatic NSCLC. All the patients were studied for EGFR mutations, ALK, and ROS-1 fusions. The outcome measures were the presence of EGFR, ALK, and ROS-1 fusions among the patients with NSCLC and the risk association with age, gender, smoking, and tumor differentiation. Results: Out of 87 patients, 26 (29.89%) patients tested positive for EGFR mutations, 4 (4.6%) for ALK, and a single case for ROS-1 fusion. The mean age of the patients who were EGFR positive was significantly younger than the mean age of those without EGFR mutation (56.77 ± 12.01 vs. 66.6..... READ ARTICLE

Journal of Radiation and Cancer Research DOI:10.4103/jrcr.jrcr_43_21

Authors: Raghav Kesri, Hari Goyal, Geetanjali Gupta, Deepak Bharti and Richu Sharma

Discovery of 2,4-pyrimidinediamine derivatives as potent dual inhibitors of ALK and HDAC

Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK positive non-small cell lung cancer (NSCLC) naïve or resistant cells. In this work, we designed and synthesized a series of 2,4-pyrimidinediamine derivatives as dual ALK and HDAC inhibitors based on pharmacophore merged strategy. Among which, compound 10f displayed the most potent and balanced inhibitory activity against ALK (IC50 = 2.1 nM) and HDAC1 (IC50 = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALKL1196M (IC50 = 1.7 nM) as well as the Ceritinib-resistant ALKG1202R (IC50 = 0.4 nM) mutants. In antiproliferative activity assay, 10f exhibited impressive activity on ALK-addicted cancer cell lines at low micromole concentrations, which was comparable to that of Crizotinib and Ceritinib. Further flow cytometric analysis indicated that 10f could effectively ind..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2021.113672

Authors: Tao Pan, Yanrong Dan, Dafeng Guo, Junhao Jiang, Dongzhi Ran, Lin Zhang, Binghua Tian, Jianyong Yuan, Yu Yu, Zongjie Gan

Pre-Clinical, group2Kirk SmithNovember 15, 2021ALK/HDAC dual Inhibitors, Pharmacophore merged strategy, NSCLC

Multiscale profiling of enzyme activity in cancer

Diverse processes in cancer are mediated by enzymes, which most proximally exert their function through their activity. Methods to quantify enzyme activity, rather than just expression, are therefore critical to our ability to understand the pathological roles of enzymes in cancer and to harness this class of biomolecules as diagnostic and therapeutic targets. Here we present an integrated set of methods for measuring specific enzyme activities across the organism, tissue, and cellular levels, which we unify into a methodological hierarchy to facilitate biological discovery. We focus on proteases for method development and validate our approach through the study of tumor progression and treatment response in an autochthonous model of Alk-mutant lung cancer. To quantitatively measure activity dynamics over time, we engineered multiplexed, peptide-based nanosensors to query protease activity in vivo. Machine learning analysis of sensor measurements revealed dramatic protease dysregulatio..... READ ARTICLE

BioRxiv DOI:10.1101/2021.11.11.468288

Authors: Ava P. Soleimany, Jesse D. Kirkpatrick, Cathy S. Wang, Alex M. Jaeger, Susan Su, Santiago Naranjo, Qian Zhong, Christina M. Cabana, Tyler Jacks, Sangeeta N. Bhatia

Review Paper, group2Kirk SmithNovember 12, 2021Multiscale profiling, enzyme activity, cancer

Hexokinases II-mediated glycolysis governs susceptibility to crizotinib in ALK-positive non-small cell lung cancer

Background

Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK+ NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK+ NSCLC cells to crizotinib requires further investigation.
Methods

The levels of glycolysis in H3122 and H2228 cells were evaluated through detection of glucose consumption and lactate production. MTT assay was used to explore the effects of glycolytic inhibitors on crizotinib sensitivity, and the potential mechanism of action were detected by colony formation, Ki67 incorporation assay, transwell assay, small interfering RNA technology and western blot analysis.
Results

ALK+ NSCLC cells exhibited significantly higher levels of glycolysis compared to ALK− NSCLC cells. Long-term exposure to crizotinib could decrease the sensitivity of ALK+ NSCLC cells to crizotinib via increasing the levels of glycolysis related to hexokinases I..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14184

Authors: Caiyu Lin, Hengyi Chen, Rui Han, Li Li, Conghua Lu, Shuai Hao, Yubo Wang, Yong He

Pre-Clinical, group2Kirk SmithNovember 2, 20212DG, glycolysis, anaplastic lymphoma kinase (ALK), crizotinib

Novel treatment of endobronchial inflammatory myofibroblastic tumor in a child

Isolated endobronchial inflammatory myofibroblatic tumors (IMT) are rare, accounting for about 1% of primary endobronchial tumors in children. The mainstay of treatment for this tumor has been surgical resection. Recently, the identification of anaplastic lymphoma kinase (ALK) gene mutations in half of the IMTs and promising results of treatment with ALK inhibitors in other ALK-positive tumors have opened the possibility of alternative approaches. We present a 4-year-old child with an ALK-positive endobronchial IMT, treated with endoscopic resection and neoadjuvant therapy with Crizotinib, without evidence of tumor recurrence 2 years after the initial resection. READ ARTICLE

Pediatric Pulmonology DOI:10.1097/CAD.0000000000001224

Authors: Jessica Reyes-Angel, Louis B. Rapkin, Jeffrey P. Simons and Hiren Muzumdar

A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residu..... READ ARTICLE

BioRxiv DOI:10.1101/2021.10.23.465573

Authors: Franziska Haderk, Celia Fernández-Méndez, Lauren Čech, Johnny Yu, Ismail M. Meraz, Victor Olivas, Dora Barbosa Rabago, D. Lucas Kerr, Carlos Gomez, David V. Allegakoen, Juan Guan, Khyati N. Shah, Kari A. Herrington, Oghenekevwe M. Gbenedio, Shigeki Nanjo, Mourad Majidi, Whitney Tamaki, Julia K. Rotow, Caroline E. McCoach, Jonathan W. Riess, J. Silvio Gutkind, Tracy T. Tang, Leonard Post, Bo Huang, Pilar Santisteban, Hani Goodarzi, Sourav Bandyopadhyay, Calvin J. Kuo, Jeroen P. Roose, Wei Wu, Collin M. Blakely, Jack A. Roth, Trever G. Bivona

Phase-separated foci of EML4-ALK facilitate signalling and depend upon an active kinase conformation

Variants of the oncogenic EML4-ALK fusion protein contain a similar region of ALK encompassing the kinase domain, but different portions of EML4. Here, we show that EML4-ALK V1 and V3 proteins form cytoplasmic foci that contain components of the MAPK, PLCγ and PI3K signalling pathways. The ALK inhibitors ceritinib and lorlatinib dissolve these foci and EML4-ALK V3 but not V1 protein re-localises to microtubules, an effect recapitulated in a catalytically inactive EML4-ALK mutant. Mutations that promote a constitutively active ALK stabilise the cytoplasmic foci even in the presence of these inhibitors. In contrast, the inhibitor alectinib increases foci formation of both wild-type and catalytically inactive EML4-ALK V3 proteins, but not a Lys-Glu salt bridge mutant. We propose that EML4-ALK foci formation occurs as a result of transient association of stable EML4-ALK trimers mediated through an active conformation of the ALK kinase domain. Our results demonstrate the formation of EML4-A..... READ ARTICLE

EMBO Reports DOI:10.15252/embr.202153693

Authors: Josephina Sampson, Mark W Richards, Jene Choi, Andrew M Fry, Richard Bayliss

Pre-Clinical, group2Kirk SmithOctober 18, 2021EML4-ALK fusion protein, variants, inhibitors, cytoplasmic foci

Targeted Therapy in a Young Adult With a Novel Epithelioid Tumor Driven by a PRRC2B-ALK Fusion

This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets. READ ARTICLE

Journal of the National Comprehensive Cancer Network DOI:10.6004/jnccn.2021.7056

Authors: Ajay Gupta, Huifei Liu, Kathleen M. Schieffer, Selene C. Koo, Catherine E. Cottrell PhD, Elaine R. Mardis, Ryan D. Roberts and Nicholas D. Yeager MD

Case Study, group2Kirk SmithOctober 15, 2021PRRC2B-ALK, abdominal mass