Two novel strategies to overcome the resistance to ALK tyrosine kinase inhibitor drugs: Macrocyclic inhibitors and proteolysis-targeting chimeras

Lung cancer is the most malignant tumor in the worldwide. About 3%-5% non-small cell lung cancer (NSCLC) patients carry anaplastic lymphoma kinase (ALK) gene fusions and receive great benefits from ALK-targeted therapy. However, drug resistance inevitably occurs even with the most potent inhibitor drug lorlatinib. About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one-third of loratinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic. Novel strategies are in great need to overcome drug resistance. Lately, two novel strategies have been developed and attracted great attentions for their potentials to overcome drug resistance problems: (1) developed small compact macrocyclic ALK kinase inhibitors and (2) developed ALK targeted proteolysis-targeting chimera (PROTAC) drugs. The macrocyclic molecules are small and compact in size, brain barrier permeable, and highly potent against lorlatinib-resistant compound mutations. Developed ALK targeted PROTAC molecules could degrade oncogenic ALK driver proteins. Some showed superiority in killing ALK positive cancer cells and inhibiting the growth of cells expressing G1202R resistant ALK proteins comparing to inhibitor drugs. The update on these two treatment strategies was reviewed. READ ARTICLE

MedComm DOI: 10.1002/mco2.42

Authors: Song X, Zhong H, Qu X, Yang L and Jiang B.

Bio-Nanocarriers for Lung Cancer Management: Befriending the Barriers

Lung cancer is a complex thoracic malignancy developing consequential to aberrations in a myriad of molecular and biomolecular signaling pathways. It is one of the most lethal forms of cancers accounting to almost 1.8 million new annual incidences, bearing overall mortality to incidence ratio of 0.87. The dismal prognostic scenario at advanced stages of the disease and metastatic/resistant tumor cell populations stresses the requisite of advanced translational interdisciplinary interventions such as bionanotechnology. This review article deliberates insights and apprehensions on the recent prologue of nanobioengineering and bionanotechnology as an approach for the clinical management of lung cancer. The role of nanobioengineered (bio-nano) tools like bio-nanocarriers and nanobiodevices in secondary prophylaxis, diagnosis, therapeutics, and theranostics for lung cancer management has been discussed. Bioengineered, bioinspired, and biomimetic bio-nanotools of considerate translational va..... READ ARTICLE

Nanomicro Letters DOI:10.1007/s40820-021-00630-6

Authors: Shruti Rawal and Mayur Patel

Treatment of brain metastases in ALK-positive Non-Small Cell Lung Cancer

Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC): they are often not amenable to surgical resection and are generally treated with radiotherapy (RT). This however causes severe late toxic side effects that may become invalidating considering the relatively long survival provided by recent medical treatment with target therapies. Several clinical trials have demonstrated that ALK-inhibitors (crizotinib, alectinib, brigatinib) show excellent activity also against brain metastases. It is therefore reasonable, in asymptomatic patients, to start treatment with specific inhibitors: RT will be used at the time of tumor progression or when symptoms appear. This sequence provides the best quality of life for patients. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2021.103400

Authors: Serena Ceddia and Giovanni Codacci-Pisanelli

Immune checkpoint inhibitors in oncogene-addicted non-small cell lung cancer: a systematic review and meta-analysis

Eighty-seven studies were included in the qualitative analysis. EGFR mutation may be a biomarker of poor response to single-agent ICIs (7% of EGFR-mutant NSCLC patients achieved disease response in prospective trials), while encouraging results have been shown with combination strategies. KRAS-mutated disease (response rate, RR, 22%) has different clinical and pathological characteristics, and the co-existence of additional mutations (e.g., STK11 or TP53) influence tumor microenvironment and response to immunotherapy. Other molecular alterations have been marginally considered prospectively, and data from clinical practice are variegated, given poor effectiveness of ICIs in ALK-rearranged disease (RR 9.5%, pooling the data of retrospective studies) or some encouraging results in BRAF-(RR 25%, retrospective data) or MET-driven one (with estimations conditioned by the presence of both exon 14 skipping mutations and gene amplification in reported series). In oncogene-addicted NSCLC (with ..... READ ARTICLE

Translational lung Cancer Research DOI:10.21037/tlcr-20-941

Authors: Giorgia Guaitoli, Marcello Tiseo, Massimo Di Maio, Luc Friboulet and Francesco Facchinetti

Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview

Over the past years, the identification of genetic alterations in oncogenic drivers in non-small cell lung cancer (NSCLC) has significantly and favorably transformed the outcome of patients who can benefit from targeted therapies such as tyrosine kinase inhibitors. Among these genetic alterations, anaplastic lymphoma kinase (ALK) rearrangements were discovered in 2007 and are present in 3–5% of patients with NSCLC. In addition, radiotherapy remains one of the cornerstones of NSCLC treatment. Moreover, improvements in the field of radiotherapy with the use of hypofractionated or ablative stereotactic radiotherapy have led to a better outcome for localized or oligometastatic NSCLC. To date, the effects of the combination of ALK inhibitors and radiotherapy are unclear in terms of safety and efficacy but could potently improve treatment. In this manuscript, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13102394

Authors: Delphine Antoni, Hélène Burckel, and Georges Noe

Review PaperKirk SmithMay 5, 2021NSCLC, ALK, TKI, radiotherapy

Thromboembolism in ALK+ and ROS1+ NSCLC patients: A systematic review and meta-analysis

In this study, we confirmed that there is an increased incidence of TTE in both ALK+ and ROS1+ NSCLC patients as compared to controls (non-ALK+ and non-ROS1+) by meta-analysis. Additionally, time-to-event analysis in this study served as a second meta-analytic method to provide dual sensitivity and confirmed similar elevated TTE risks among ALK+ and ROS1+ NSCLC patients. VTE (primarily PE and DVT) is the primary TE event of interest investigated in the studies included in this systematic review. In general, this meta-analysis indicated there is about a 2.5-fold and slightly higher than 3-fold increase in VTE among ALK+ and ROS1+ patients, respectively when compared to non-ALK+ and non-ROS1+ NSCLC patients. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.05.019

Authors: Viola W. Zhu, Joseph J. Zhao, Yanfei Gao, Nicholas L. Syn, Shannon S. Zhang, Sai-Hong Ignatius Ou, Kenneth A. Bauer, Misako Nagasaka

Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study.

Early ctDNA dynamics may predict lorlatinib efficacy in pts with previously untreated ALK-positive NSCLC. The magnitude of reduction in ctDNA at 4 weeks may be associated with better responses and potentially longer PFS. These findings further support the utility of dynamic ctDNA monitoring in ALK-positive NSCLC. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_SUPPL.9011

Authors: Ross A. Soo, Jean-Francois Martini, Anthonie J. van der Wekken, Shunsuke Teraoka, Alice T. Shaw, Deborah Shepard, Anna Maria Calella, Anna Polli, Francesca Toffalorio, Pascale Tomasini, Chao-Hua Chiu, Dariusz Kowalski, Hye Ryun Kim, Benjamin J. Solomon

Review PaperKirk SmithMay 1, 2021lorlatinib, CROWN study, ctDNA

Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Lung cancer (LCa) remains the leading cause of cancer-related mortality worldwide,
with late diagnosis and limited therapeutic approaches still constraining patient’s outcome. In recent years,
liquid biopsies have significantly improved the disease characterization and brought new insights into
LCa diagnosis and management. The integration of microfluidic devices in liquid biopsies have shown
promising results regarding circulating biomarkers isolation and analysis and these tools are expected to
establish automatized and standardized results for liquid biopsies in the near future. Herein, we review the
status of lab-on-a-chip approaches for liquid biopsies in LCa and highlight their current applications for
circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) research and clinical validation studies. READ ARTICLE

Cancers DOI:10.3390/cancers13092101

Authors: Carvalho, Â., Ferreira, G., Seixas, D., Guimarães-Teixeira, C., Henrique, R., Monteiro, F.J., Jerónimo, C.

Review PaperKirk SmithApril 27, 2021inflammatory myofibroblastic tumors, IMT, rare ALK fusions

Entrectinib: A Review in NTRK+ Solid Tumours and ROS1+ NSCLC

Entrectinib expands the range of treatment options for advanced NTRK+ solid tumours and ROS1+ NSCLC, and may be of particular value in patients with existing CNS metastases and those who are at risk of developing CNS metastases. READ ARTICLE

Drugs DOI:10.6084/m9.figshare.14150207

Authors: James E Frampton

Review PaperKirk SmithApril 19, 2021Entrectinib, ROS1, NTRK

Molecular diagnosis in non-small-cell lung cancer: expert opinion on ALK and ROS1 testing

The effectiveness of targeted therapies with tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) depends on the accurate determination of the genomic status of the tumour. For this reason, molecular analyses to detect genetic rearrangements in some genes (ie, ALK, ROS1, RET and NTRK) have become standard in patients with advanced disease. Since immunohistochemistry is easier to implement and interpret, it is normally used as the screening procedure, while fluorescence in situ hybridisation (FISH) is used to confirm the rearrangement and decide on ambiguous immunostainings. Although FISH is considered the most sensitive method for the detection of ALK and ROS1 rearrangements, the interpretation of results requires detailed guidelines. In this review, we discuss the various technologies available to evaluate ALK and ROS1 genomic rearrangements using these techniques. Other techniques such as real-time PCR and next-generation sequencing have been developed recently to evaluat..... READ ARTICLE

Journal of Clinical Pathology DOI:10.1136/jclinpath-2021-207490

Authors: Esther Conde, Federico Rojo, Javier Gómez, Ana Belén Enguita, Ihab Abdulkader, Ana González, Dolores Lozano, Nuria Mancheño, Clara Salas, Marta Salido, Eduardo Salido-Ruiz, Enrique de Álava

Review PaperKirk SmithApril 1, 2021ALK, ROS1, molecular diagnosis

Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.

These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC. READ ARTICLE

Clinical Cancer Research DOI: 10.1158/1078-0432.ccr-20-2853

Authors: Azusa Tanimoto, Shingo Matsumoto, Shinji Takeuchi, Sachiko Arai, Koji Fukuda, Akihiro Nishiyama, Kiyotaka Yoh, Takaya Ikeda, Naoki Furuya, Kazumi Nishino, Yuichiro Ohe, Koichi Goto and Seiji Yano

Review PaperKirk SmithMarch 1, 2021Review Papers

Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches

Review Paper describing the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. Reports pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describes the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13061476

Authors: Kamya Sankar, Sunitha Nagrath, Nithya Ramnath

Review PaperKirk SmithMarch 1, 2021ALK, ALK-rearrangements, NSCLC, TKI, immune evasion, immunotherapy, cancer vaccine

Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC. READ ARTICLE

Cancers DOI: 10.3390/cancers13040699

Authors: Elisabeth Smolle, Valentin Taucher, Joerg Lindenmann, Philipp J. Jost, Martin Pichler

Challenges of diagnostic genomics in Latin America

Cancer genome sequencing methods have now become essential for diagnostic purposes, for devising treatment strategies, and for monitoring disease regression and progression. However, access to these benefits has not permeated homogeneously throughout the world; certain regions, such as Latin America, have been slower at adopting these technologies in terms of their routine use, development and patient access. There are also differences among Latin American subregions with respect to their prioritized types of neoplasia and the drugs that are available and approved in them. An overview of the current situation, including the status of genomics for cancer diagnostics and efforts by type of cancer is presented. In addition, we discuss the perspective of initiatives, alliances, and educational/research programs that pledge to make cancer genomics diagnosis a reality for Latin American individuals’ health. READ ARTICLE

Current Opinion in Genetics & Development DOI:10.1016/j.gde.2020.12.010

Authors: Rosa Maria Alvarez-Gomez, Marcela Angelica De la Fuente-Hernandez, Luis Herrera-Montalvo and Alfredo Hidalgo-Miranda

Review PaperKirk SmithJanuary 28, 2021Latin America, cancer genomics

Therapeutic Sequencing in ALK+ NSCLC

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a cur..... READ ARTICLE

Pharmaceuticals DOI: 10.3390/ph14020080

Authors: Elsayed M., Christopoulos P.

Review PaperKirk SmithJanuary 21, 2021ALK, NSCLC, TKI, EML4-ALK fusion variant 3, chemotherapy, sequential treatment

Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice

The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification. READ ARTICLE

Cells DOI:10.3390/cells10010168

Authors: Paul Hofman

Review PaperKirk SmithJanuary 15, 2021liquid biopsy, lung cancer, ALK, resistance, targeted therapy

Therapeutic Strategies to Overcome ALK Resistance in Cancer

Therapeutic Strategies to Overcome ALK Resistance in Cancer, Volume 13, presents current strategies to improve and prolong clinical benefit in ALK driven cancers. Most patients with ALK-driven cancer are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops. This book discusses topics such as structure and function of ALK, ALK rearranged lung cancer, resistance mechanisms to ALK TKI tumors, and novel therapeutic strategies to enhance crizotinib anti-tumor efficacy in ALCL. Additionally, it encompasses information on drug combinations to enhance ALK TKI anti-tumor efficacy in neuroblastoma and future perspectives in the field. This book is a valuable resource for cancer researchers, clinicians and several members of biomedical field who need to understand more about how to fight ALK resistance in cancer treatment. READ ARTICLE

Academic Press DOI: 10.1016/C2019-0-03295-5

Edited by: Luc Friboulet

NPM-ALK: A Driver of Lymphoma Pathogenesis and a Therapeutic Target

Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is th..... READ ARTICLE

Cancers (Basel) DOI:10.3390/cancers13010144

Authors: Elissa Andraos, Joséphine Dignac, Fabienne Meggetto

Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma

Lung cancer is one of the most common malignant neoplasms. As a result of the disease’s progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies—neurosurgery and radiation therapy—do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)—activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes ..... READ ARTICLE

International Journal of Molecular Science DOI:10.3390/ijms22020593

Authors: Agnieszka Rybarczyk-Kasiuchnicz, Rodryg Ramlau, and Katarzyna Stencel

Upfront Management of ALK-Rearranged Metastatic Non-small Cell Lung Cancer: One Inhibitor Fits All?

During the past 10 years, multiple ALKi have been developed, and four different compounds are currently available as upfront options for ALK+ NSCLC patients: crizotinib, ceritinib, alectinib, and brigatinib. Second-generation (2G) ALKi demonstrated superior clinical activity in terms of median progression-free survival (mPFS), objective response rate (ORR), intracranial disease control, and duration of response (DOR) when compared with crizotinib. 2G ALKi represent the current gold-standard first-line treatment for ALK-rearranged metastatic NSCLC. Among all available options, in our opinion, alectinib has likely the best profile of clinical activity and safety, thus emerging as the best upfront therapy. More insights will come from ongoing trials and analysis of biomarkers. READ ARTICLE

Current Oncology Reports DOI: 10.1007/s11912-020-00989-6

Authors: Febrizio Tabbò, Francesco Passiglia, Silvia Novello

Review PaperKirk SmithJanuary 1, 2021ALK, NSCLC, TKIs, biomarkers