Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes

Hudson, Sandra; Wang, Dongliang; Middleton, Frank A.; Nevaldine, Barbara; Hutchison, Robert

doi:10.1002/pbc.27094

Cited by 8 publications

(6 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data collectively demonstrate that an upfront combination of targeted and cytotoxic therapies might be beneficial in the treatment of ALK+ ALCL. This is further corroborated by recent results of brentuximab+chemotherapy combinations in newly diagnosed ALK+ ALCL patients [4,51] and promising in vitro data on crizotinib+brentuximab association [52]. Moreover, the meaning of this work extends to a wider scope since the combinatorial approach represents a relevant strategy in all clinical fields for which resistance represents an urgent problem to be solved.…”

Section: Discussionsupporting

confidence: 77%

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Arosio

Sharma

Villa

et al. 2021

Cancers

View full text Add to dashboard Cite

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

show abstract

Section: Discussionsupporting

confidence: 77%

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Arosio

Sharma

Villa

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Indeed, studies have shown that crizotinib synergizes with brentuximab vedotin, which targets CD30-expressing cells, despite NPM-ALK having been shown to drive CD30 expression. 59 ALK inhibitors are now being added to frontline therapy 60 (e.g., in trial NCT01979536) although this combination has led to some unexpected toxicity. 11 NOTCH1 inhibition may therefore serve as a second-line treatment.…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target

et al. 2020

View full text Add to dashboard Cite

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

show abstract

“…Crizotinib is being evaluated in combination with cytotoxic chemotherapy as a part of front‐line therapy in patients with ALK+ALCL (NCT01979536). In vitro studies have shown synergistic activity with crizotinib and brentuximab vedotin and clinical studies are being designed evaluating this combination 130 …”

Section: Principles Of Managing Ptclmentioning

confidence: 99%

Aggressive T‐cell lymphomas: 2024: Updates on diagnosis, risk stratification, and management

Ong,

Zain

2024

American J Hematol

View full text Add to dashboard Cite

IntroductionAggressive T‐cell lymphomas continue to have a poor prognosis. There are over 30 different subtypes of peripheral T‐cell lymphoma (PTCL), and we are now beginning to understand the differences between the various subtypes beyond histologic variations.Molecular Pathogenesis of Various Subtypes of PTCLGene expression profiling and other molecular techniques have enabled deeper understanding of differences in various subtypes as reflected in the latest 5th WHO classification of PTCL. It is becoming increasingly clear that therapeutic approaches that target specific cellular pathways are needed to improve the clinical outcomes of PTCL.Targeted TherapiesThere are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. This includes the CD30 directed antibody drug conjugate brentuximab vedotin. Other notable targets are phosphatidylinositol 3‐kinase inhibitors, histone deacetylase inhibitors, CD25, and chemokine receptor 4. Anaplastic lymphoma kinase (ALK) inhibitors are promising for ALK expressing tumors.ImmunotherapiesAllogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL. The use of checkpoint inhibitors in the treatment of PTCL is still controversial, with best results seen in cases of extranodal natural killer cell/T‐cell lymphoma. Bispecific antibody‐based treatments and chimeric antigen receptor cell‐based therapies are in clinical trials.

show abstract

Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes

Cited by 8 publications

References 72 publications

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target

Aggressive T‐cell lymphomas: 2024: Updates on diagnosis, risk stratification, and management

Contact Info

Product

Resources

About