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Ref Type Journal Article
PMID (22322295)
Authors Mahajan K, Coppola D, Chen YA, Zhu W, Lawrence HR, Lawrence NJ, Mahajan NP
Title Ack1 tyrosine kinase activation correlates with pancreatic cancer progression.
Journal The American journal of pathology
Vol 180
Issue 4
Date 2012 Apr
URL
Abstract Text Pancreatic cancer is a significant cause of cancer mortality worldwide as the disease has advanced significantly in patients before symptoms are evident. The signal transduction pathways that promote this rapid progression are not well understood. Ack1 or TNK2, an ubiquitously expressed oncogenic non-receptor tyrosine kinase, integrates signals from ligand-activated receptor tyrosine kinases to modulate intracellular signaling cascades. In the present study, we investigated the Ack1 activation profile in a pancreatic cancer tumor microarray, and observed that expression levels of activated Ack1 and pTyr284-Ack1 positively correlated with the severity of disease progression and inversely correlated with the survival of patients with pancreatic cancer. To explore the mechanisms by which Ack1 promotes tumor progression, we investigated the role of AKT/PKB, an oncogene and Ack1-interacting protein. Ack1 activates AKT directly in pancreatic and other cancer cell lines by phosphorylating AKT at Tyr176 to promote cell survival. In addition, the Ack1 inhibitor AIM-100 not only inhibited Ack1 activation but also suppressed AKT tyrosine phosphorylation, leading to cell cycle arrest in the G1 phase. This effect resulted in a significant decrease in the proliferation of pancreatic cancer cells and induction of apoptosis. Collectively, our data indicate that activated Ack1 could be a prognostic marker for ascertaining early or advanced pancreatic cancer. Thus, Ack1 inhibitors hold promise for therapeutic intervention to inhibit pancreatic tumor growth.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
AIM-100 AIM-100 3 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AIM-100 AIM 100 TNK2 Inhibitor 6 AIM-100 is a small molecule inhibitor of Tnk2 (Ack1), which may lead to increased apoptosis and decreased proliferation of tumor cells (PMID: 22322295, PMID: 20623637, PMID: 31228486).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown ovarian cancer not applicable AIM-100 Preclinical Actionable In a preclinical study, AIM-100 inhibited growth of ovarian cancer cells in culture (PMID: 22322295). 22322295
Unknown unknown pancreatic cancer not applicable AIM-100 Preclinical Actionable In a preclinical study, treatment with AIM-100 resulted in increased apoptosis and decreased growth of pancreatic cancer cells in culture (PMID: 22322295). 22322295
Unknown unknown breast cancer not applicable AIM-100 Preclinical Actionable In a preclinical study, AIM-100 inhibited growth of breast cancer cells in culture (PMID: 22322295). 22322295