ArticleBlood2022
Tyrosine phosphatases regulate resistance to ALK inhibitors in ALK+ anaplastic large cell lymphoma.
Article in Blood, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 48 citations in OpenAlex.
- T cell lymphomas: cancers of aberrant immune synapse signalling.Nature reviews. Immunology · 2026Review
- CircRNAs derived from the tyrosine phosphatase PTPN22 impact chemosensitivity in ALK-positive T-cell lymphomas.Scientific reports · 2026Article
- A system-wide investigation into the phosphoregulatory network of TNIK and its cellular implications.Frontiers in bioinformatics · 2026Article
- BH3 mimetic drugs overcome the microenvironment-induced resistance to crizotinib in ALK+ anaplastic large cell lymphoma.Blood advances · 2025Article
- Common origins of autoimmune diseases and lymphoid malignancies.Trends in immunology · 2025Review
- Fusion genes in cancers: Biogenesis, functions, and therapeutic implications.Genes & diseases · 2025Review
- PTPN2 Inhibition Disrupts Mitochondrial Renewal and Blocks TFRC-Mediated Mitophagy to Exert Anti-Tumor Activities in ALK-Positive Anaplastic Large Cell Lymphoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy.Leukemia · 2025Article
- ALK in cancer: from function to therapeutic targeting.Nature reviews. Cancer · 2025Review
- Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer.Cell death & disease · 2024Article
- Anaplastic Lymphoma Kinase (ALK) Inhibitors Enhance Phagocytosis Induced by CD47 Blockade in Sensitive and Resistant ALK-Driven Malignancies.Biomedicines · 2024Article
- Recurrent somatic mutations of FAT family cadherins induce an aggressive phenotype and poor prognosis in anaplastic large cell lymphoma.British journal of cancer · 2024Article
- Identification of APBB1 as a substrate for anaplastic lymphoma kinase.Journal of biochemistry · 2024Article
- GeneRaMeN enables integration, comparison, and meta-analysis of multiple ranked gene lists to identify consensus, unique, and correlated genes.Briefings in bioinformatics · 2024Article
- From Tyrosine Kinases to Tyrosine Phosphatases: New Therapeutic Targets in Cancers and Beyond.Pharmaceutics · 2024Review
- STAT3 couples activated tyrosine kinase signaling to the oncogenic core transcriptional regulatory circuitry of anaplastic large cell lymphoma.Cell reports. Medicine · 2024Article
- Review
- Case report: Musculoskeletal metastastic inflammatory myofibroblastic tumor (IMT) treated by sequential ALK-TKI with longterm response.Frontiers in oncology · 2024Article
- ALK fusions in the pan-cancer setting: another tumor-agnostic target?NPJ precision oncology · 2023Review
- Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma.Science translational medicine · 2023Article
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Authors and funding
20 authors at 7 institutions in 5 countries.
Funding
Abstract
Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.