Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.

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Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC

Journal of Personalized Medicine ◽

10.3390/jpm10030107 ◽

2020 ◽

Vol 10 (3) ◽

pp. 107 ◽

Cited By ~ 2

Author(s):

László Urbán ◽

Róbert Dóczi ◽

Barbara Vodicska ◽

Dóra Kormos ◽

László Tóth ◽

...

Keyword(s):

Kinase Inhibitors ◽

Nsclc Patient ◽

Resistance Mechanisms ◽

Tumor Control ◽

Next Generation ◽

Alk Inhibitors ◽

Anaplastic Lymphoma ◽

Alk Inhibitor ◽

Alk Positive ◽

Inhibitor Treatment

Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. Results: The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. Conclusion: TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms.

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The Tumor Suppressor MTUS1/ATIP1 Modulates Tumor Promotion in Glioma: Association with Epigenetics and DNA Repair

Cancers ◽

10.3390/cancers13061245 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1245

Author(s):

Nikhil Ranjan ◽

Vimal Pandey ◽

Manas Kumar Panigrahi ◽

Lukas Klumpp ◽

Ulrike Naumann ◽

...

Keyword(s):

High Grade Glioma ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Tumor Resistance ◽

Tumor Irradiation ◽

Damage Repair ◽

Low Passage ◽

Novel Therapeutic Strategies

Glioblastoma (GBM) is a highly aggressive brain tumor. Resistance mechanisms in GBM present an array of challenges to understand its biology and to develop novel therapeutic strategies. We investigated the role of a TSG, MTUS1/ATIP1 in glioma. Glioma specimen, cells and low passage GBM sphere cultures (GSC) were analyzed for MTUS1/ATIP1 expression at the RNA and protein level. Methylation analyses were done by bisulfite sequencing (BSS). The consequence of chemotherapy and irradiation on ATIP1 expression and the influence of different cellular ATIP1 levels on survival was examined in vitro and in vivo. MTUS1/ATIP1 was downregulated in high-grade glioma (HGG), GSC and GBM cells and hypermethylation at the ATIP1 promoter region seems to be at least partially responsible for this downregulation. ATIP1 overexpression significantly reduced glioma progression by mitigating cell motility, proliferation and facilitate cell death. In glioma-bearing mice, elevated MTUS1/ATIP1 expression prolonged their survival. Chemotherapy, as well as irradiation, recovered ATIP1 expression both in vitro and in vivo. Surprisingly, ATIP1 overexpression increased irradiation-induced DNA-damage repair, resulting in radio-resistance. Our findings indicate that MTUS1/ATIP1 serves as TSG-regulating gliomagenesis, progression and therapy resistance. In HGG, higher MTUS1/ATIP1 expression might interfere with tumor irradiation therapy.

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Development of Resistance in Wild-Type and Hypermutable Pseudomonas aeruginosa Strains Exposed to Clinical Pharmacokinetic Profiles of Meropenem and Ceftazidime Simulated In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00160-07 ◽

2007 ◽

Vol 51 (10) ◽

pp. 3642-3649 ◽

Cited By ~ 19

Author(s):

Beate Henrichfreise ◽

Irith Wiegand ◽

Ingeborg Luhmer-Becker ◽

Bernd Wiedemann

Keyword(s):

Pseudomonas Aeruginosa ◽

Parent Strain ◽

Resistance Mechanisms ◽

In Vitro Models ◽

Wild Type ◽

Resistance Development ◽

Development Of Resistance ◽

Pharmacokinetic Profiles ◽

Mutant Prevention Concentration

ABSTRACT In this study we investigated the interplay of antibiotic pharmacokinetic profiles and the development of mutation-mediated resistance in wild-type and hypermutable Pseudomonas aeruginosa strains. We used in vitro models simulating profiles of the commonly used therapeutic drugs meropenem and ceftazidime, two agents with high levels of antipseudomonal activity said to have different potentials for stimulating resistance development. During ceftazidime treatment of the wild-type strain (PAO1), fully resistant mutants overproducing AmpC were selected rapidly and they completely replaced wild-type cells in the population. During treatment with meropenem, mutants of PAO1 were not selected as rapidly and showed only intermediate resistance due to the loss of OprD. These mutants also replaced the parent strain in the population. During the treatment of the mutator P. aeruginosa strain with meropenem, the slowly selected mutants did not accumulate several resistance mechanisms but only lost OprD and did not completely replace the parent strain in the population. Our results indicate that the commonly used dosing regimens for meropenem and ceftazidime cannot avoid the selection of mutants of wild-type and hypermutable P. aeruginosa strains. For the treatment outcome, including the prevention of resistance development, it would be beneficial for the antibiotic concentration to remain above the mutant prevention concentration for a longer period of time than it does in present regimens.

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Emerging Paradigms in the Development of Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2012.45.2029 ◽

2013 ◽

Vol 31 (31) ◽

pp. 3987-3996 ◽

Cited By ~ 198

Author(s):

Justin F. Gainor ◽

Alice T. Shaw

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Genetic Alterations ◽

Anaplastic Lymphoma ◽

Development Of Resistance ◽

Tki Resistance ◽

Alk Positive ◽

Egfr Mutant

The success of tyrosine kinase inhibitors (TKIs) in select patients with non–small-cell lung cancer (NSCLC) has transformed management of the disease, placing new emphasis on understanding the molecular characteristics of tumor specimens. It is now recognized that genetic alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) define two unique subtypes of NSCLC that are highly responsive to genotype-directed TKIs. Despite this initial sensitivity, however, the long-term effectiveness of such therapies is universally limited by the development of resistance. Identifying the mechanisms underlying this resistance is an area of intense, ongoing investigation. In this review, we provide an overview of recent experience in the field, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens. Although diverse TKI resistance mechanisms have been identified within EGFR-mutant and ALK-positive patients, we highlight common principles of resistance shared between these groups. These include the development of secondary mutations in the kinase target, gene amplification of the primary oncogene, and upregulation of bypass signaling tracts. In EGFR-mutant and ALK-positive patients alike, acquired resistance may also be a dynamic and multifactorial process that may necessitate the use of treatment combinations. We believe that insights into the mechanisms of TKI resistance in patients with EGFR mutations or ALK rearrangements may inform the development of novel treatment strategies in NSCLC, which may also be generalizable to other kinase-driven malignancies.

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Targeting Oncogenic BRAF: Past, Present, and Future

Cancers ◽

10.3390/cancers11081197 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1197 ◽

Cited By ~ 24

Author(s):

Zaman ◽

Wu ◽

Bivona

Keyword(s):

Kinase Inhibitors ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Genetic Alterations ◽

Therapeutic Strategies ◽

Wild Type ◽

Braf Mutations ◽

Molecular Alterations ◽

Mutant Braf

Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a “precision medicine” paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.

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Discovery of novel anaplastic lymphoma kinase inhibitors: Structure and energy-based pharmacophore strategy

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633619500147 ◽

2019 ◽

Vol 18 (03) ◽

pp. 1950014 ◽

Cited By ~ 3

Author(s):

Nivya James ◽

V. Shanthi ◽

K. Ramanathan

Keyword(s):

Lung Cancer ◽

Anaplastic Lymphoma Kinase ◽

Density Functional ◽

Kinase Inhibitors ◽

Chemical Reactivity ◽

Pharmacophore Model ◽

Density Functional Theory Calculations ◽

Alk Inhibitors ◽

Anaplastic Lymphoma ◽

Glide Docking

The clinical outcomes in patients with non-small cell lung cancer have improved, as a result of anaplastic lymphoma kinase (ALK) inhibition. Therefore in the current study, substantial effort has been made to identify ALK inhibitors through systematic virtual screening experiment consisting of e-pharmacophore and pharmacophore perception techniques. Initially, a pharmacophore model (AAAHP.193) and an e-pharmacophore model (DDRRR) encompassing the whole dataset of 12 known ALK inhibitors were developed. The hypotheses could retrieve effective compounds from DrugBank database (8621 molecules), which were then subjected to molecular docking and ADME prediction. These approaches resulted in the identification of five hits, namely, nebivolol, HDY, D42, 796, and LZE having higher Glide docking scores and promising ADME properties with augmented CNS involvement. Moreover, molecular dynamics simulations were performed to validate the inhibitory activity of the hit compounds, and density functional theory calculations were carried out to scrutinize the chemical reactivity of the hits. Subsequent interaction and scaffold analysis identified prominent interactions of the hits with ALK kinase domain and scaffolds with anti-tumor activity against lung cancer cell lines. We strongly believe that the study provides an outlook for the sighting of novel and potent ALK inhibitors in the near future.

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Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Cancers ◽

10.3390/cancers12030608 ◽

2020 ◽

Vol 12 (3) ◽

pp. 608 ◽

Cited By ~ 6

Author(s):

Marta Mariniello ◽

Raffaella Petruzzelli ◽

Luca G. Wanderlingh ◽

Raffaele La Montagna ◽

Annamaria Carissimo ◽

...

Keyword(s):

Amphotericin B ◽

Therapeutic Potential ◽

Synthetic Lethality ◽

Resistance Mechanisms ◽

Ovarian Cancer Cells ◽

Tumor Resistance ◽

Development Of Resistance ◽

Wide Range ◽

Important Challenge ◽

Approved Drugs

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.

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Antifungal Resistance Regarding Malassezia pachydermatis: Where Are We Now?

Journal of Fungi ◽

10.3390/jof6020093 ◽

2020 ◽

Vol 6 (2) ◽

pp. 93

Author(s):

Andrea Peano ◽

Elizabeth Johnson ◽

Elisa Chiavassa ◽

Paolo Tizzani ◽

Jacques Guillot ◽

...

Keyword(s):

Treatment Failure ◽

Antifungal Agents ◽

Standard Procedure ◽

Resistance Mechanisms ◽

Antifungal Resistance ◽

Antifungal Drugs ◽

Malassezia Pachydermatis ◽

Development Of Resistance ◽

Ear Canals

Malassezia pachydermatis is a yeast inhabiting the skin and ear canals in healthy dogs. In the presence of various predisposing conditions it can cause otitis and dermatitis, which are treated with multiple antifungal agents, mainly azole derivatives. This manuscript aims to review the available evidence regarding the occurrence of resistance phenomena in this organism. Various findings support the capacity of M. pachydermatis for developing resistance. These include some reports of treatment failure in dogs, the reduced antifungal activity found against yeast isolates sampled from dogs with exposure to antifungal drugs and strains exposed to antifungal agents in vitro, and the description of resistance mechanisms. At the same time, the data reviewed may suggest that the development of resistance is a rare eventuality in canine practice. For example, only three publications describe confirmed cases of treatment failure due to antifungal resistance, and most claims of resistance made by past studies are based on interpretive breakpoints that lack sound support from the clinical perspective. However, it is possible that resistant cases are underreported in literature, perhaps due to the difficulty of obtaining a laboratory confirmation given that a standard procedure for susceptibility testing of M. pachydermatis is still unavailable. These considerations highlight the need for maintaining surveillance for the possible emergence of clinically relevant resistance, hopefully through a shared strategy put in place by the scientific community.

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Pharmacological interactions of TKIs with the P-gp drug transport protein.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2536 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2536-2536 ◽

Cited By ~ 1

Author(s):

Sandra Roche ◽

Kasper Pedersen ◽

Grainne Dunne ◽

Denis Collins ◽

Aoife Devery ◽

...

Keyword(s):

Drug Resistance ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Drug Transport ◽

Kinase Inhibitors ◽

Resistance Mechanisms ◽

Cancer Drug ◽

Clear Understanding ◽

Pharmacological Interactions

2536 Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug transport proteins. P-gp is a transporter with two important roles in cancer drug therapy. If overexpressed in tumour cells it can cause drug resistance. However, P-gp, expressed in tissues as part of normal drug clearance mechanisms, is also involved in termination of drug action. Hence, TKI-mediated interactions with P-gp have significant therapeutic consequences. Methods: P-gp over-expressing cancer cell lines were used to determine the inhibitor or substrate status of tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib). Cell proliferation assays in combination with a potent P-gp inhibitor, or P-gp substrate were also employed. Findings were augmented using LC-MS-based quantitation of cellular levels of target drugs. Results: We summarise our findings of four distinct interactions with P-gp among various TKIs. Some agents have little interaction at conventional doses; others can act as P-gp inhibitors without being substrates; substrates without being inhibitors or substrates which also prevent the actions of the transporter.Eachof the investigated TKIs has a distinct relationship with P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is a substrate but not an inhibitor, while pazopanib has little interaction with P-gp. Other agents also have an effect on or are affected by P-gp to varying amounts with some of these interactions likely to be suprapharmacological. Conclusions: P-gp protein has important roles both in resistance and drug toxicology, hence, a clear understanding of the interaction of emerging drugs with this transporter is vital. Agents which are inhibitors of P-gp may have applications in drug resistance circumvention but may also greatly exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics; conversely the activity of P-gp substrate TKIs may be reduced by tumour overexpression of the transporter. Hence in vitro screening of TKI-transporter interactions may identify putative TKI resistance mechanisms, help guide the development of combination schedule trials and/or reducing unwanted treatment side effects.

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Recent Patents on the Development of c-Met Kinase Inhibitors

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892815666200630102344 ◽

2020 ◽

Vol 15 (3) ◽

pp. 228-238 ◽

Cited By ~ 1

Author(s):

Xiangming Xu ◽

Lei Yao

Keyword(s):

Natural Products ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Research Progress ◽

Science Literature ◽

Tumor Resistance ◽

Mesenchymal Epithelial Transition Factor ◽

Factor C

Background : Receptor Tyrosine Kinases (RTKs) play critical roles in a variety of cellular processes including growth, differentiation and angiogenesis, and in the development and progression of many types of cancer. Mesenchymal-Epithelial Transition Factor (c-Met) kinase is one of the types of RTKs and has become an attractive target for anti-tumor drug designing. c-Met inhibitors have a broad prospect in tumor prevention, chemotherapy, biotherapy, and especially in tumor resistance. Objective: The purpose of this article is to review recent research progress of c-Met inhibitors reported in patents since 2015. Methods: A comprehensive Scifinder and Web of Science literature review was conducted to identify all c-Met inhibitors published in patents since 2015. Results: There are two kinds of c-Met inhibitors, one is from natural products, and the other one is of synthetic origin. Most of these c-Met inhibitors show potent in vivo and in vitro antitumor activities and have potential in the treatment of cancers. Conclusion: c-Met kinase inhibitors have emerged as an exciting new drug class for the treatment of all kinds of cancers, especially the Non-Small Cell Lung Cancer (NSCLC) with tumor resistance. More studies should be conducted on natural products to find novel c-Met kinase inhibitors.

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