Resistance of Cancer Cells to Targeted Therapies Through the Activation of Compensating Signaling Loops
Viktoria von Manstein,Chul Min Yang,Diane Richter,Natalia Delis,Vida Vafaizadeh,Bernd Groner +5 more
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TLDR
The treatment of HNSCC with a specific inhibitor of c-Src initially resulted in reduced Stat3 and Stat5 activation and subsequently an arrest of cell proliferation and increased apoptosis, indicating that the inhibition of a single tyrosine kinase might not be sufficient to induce lasting therapeutic effects in cancer patients.Abstract:
The emergence of low molecular weight kinase inhibitors as “targeted” drugs has led to remarkable advances in the treatment of cancer patients. The clinical benefits of these tumor therapies, however, vary widely in patient populations and with duration of treatment. Intrinsic and acquired resistance against such drugs limits their efficacy. In addition to the well studied mechanisms of resistance based upon drug transport and metabolism, genetic alterations in drug target structures and the activation of compensatory cell signaling have received recent attention. Adaptive responses can be triggered which counteract the initial dependence of tumor cells upon a particular signaling molecule and allow only a transient inhibition of tumor cell growth. These compensating signaling mechanisms are often based upon the relief of repression of regulatory feedback loops. They might involve cell autonomous, intracellular events or they can be mediated via the secretion of growth factor receptor ligands into the tumor microenvironment and signal induction in an auto- or paracrine fashion. The transcription factors Stat3 and Stat5 mediate the biological functions of cytokines, interleukins and growth factors and can be considered as endpoints of multiple signaling pathways. In normal cells this activation is transient and the Stat molecules return to their non-phosphorylated state within a short time period. In tumor cells the balance between activating and de-activating signals is disturbed resulting in the persistent activation of Stat3 or Stat5. The constant activation of Stat3 induces the expression of target genes, which cause the proliferation and survival of cancer cells, as well as their migration and invasive behavior. Activating components of the Jak-Stat pathway have been recognized as potentially valuable drug targets and important principles of compensatory signaling circuit induction during targeted drug treatment have been discovered in the context of kinase inhibition studies in HNSCC cells [1]. The treatment of HNSCC with a specific inhibitor of c-Src, initially resulted in reduced Stat3 and Stat5 activation and subsequently an arrest of cell proliferation and increased apoptosis. However, the inhibition of c-Src only caused a persistent inhibition of Stat5, whereas the inhibition of Stat3 was only transient. The activation of Stat3 was restored within a short time period in the presence of the c-Src inhibitor. This process is mediated through the suppression of P-Stat5 activity and the decrease in the expression of the Stat5 dependent target gene SOCS2, a negative regulator of Jak2. Jak2 activity is enhanced upon SOCS2 downregulation and causes the reactivation of Stat3. A similar observation has been made upon inhibition of Bmx, bone marrow kinase x-linked, activated in the murine glioma cell lines Tu-2449 and Tu-9648. Its inhibition resulted in a transient decrease of P-Stat3 and the induction of a compensatory Stat3 activation mechanism, possibly through the relief of negative feedback inhibition and Jak2 activation. These observations indicate that the inhibition of a single tyrosine kinase might not be sufficient to induce lasting therapeutic effects in cancer patients. Compensatory kinases and pathways might become activated and maintain the growth and survival of tumor cells. The definition of these escape pathways and their preemptive inhibition will suggest effective new combination therapies for cancer.read more
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CA : A Cancer Journal for Clinicians
Patrizia Agostinis,Kristian Berg,Keith A. Cengel,Thomas H. Foster,Albert W. Girotti,Sandra O. Gollnick,Stephen M. Hahn,Michael R. Hamblin,Asta Juzeniene,David Kessel,Mladen Korbelik,Johan Moan,Pawel Mroz,Dominika Nowis,Jacques Piette,Brian C. Wilson,Jakub Golab +16 more
Journal ArticleDOI
Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies.
Aaron D. Simpson,Wilfride Petnga,Valentine M. Macaulay,Ulrike Weyer-Czernilofsky,Thomas Bogenrieder,Thomas Bogenrieder +5 more
TL;DR: The preclinical and clinical experience with IGF-targeted therapies to-date are reviewed, and the rationale for future combination approaches as a means to overcome treatment resistance is discussed.
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Ruxolitinib + capecitabine in advanced/metastatic pancreatic cancer after disease progression/intolerance to first-line therapy: JANUS 1 and 2 randomized phase III studies.
Herbert Hurwitz,Eric Van Cutsem,Johanna C. Bendell,Manuel Hidalgo,Chung Pin Li,Chung Pin Li,Marcelo Garrido Salvo,Teresa Macarulla,Vaibhav Sahai,Ashwin Reddy Sama,Edward W Greeno,Kenneth H. Yu,Chris Verslype,Fitzroy Dawkins,Christopher James Walker,Jason Clark,Eileen M. O'Reilly,Eileen M. O'Reilly +17 more
TL;DR: Ruxolitinib plus capecitabine was well tolerated in refractory pancreatic cancer patients; this combination did not improve survival.
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Raj Bhayadia,Kathrin Krowiorz,Nadine Haetscher,Razan Jammal,Stephan Emmrich,Askar Obulkasim,Jan Fiedler,Adrian Schwarzer,Arefeh Rouhi,Michael Heuser,Susanne Wingert,Sabrina Bothur,Konstanze Döhner,Tobias Mätzig,Michelle Ng,Dirk Reinhardt,Hartmut Döhner,C. Michel Zwaan,Marry M. Van den Heuvel Eibrink,Dirk Heckl,Maarten Fornerod,Thomas Thum,R. Keith Humphries,Michael A. Rieger,Florian Kuchenbauer,Jan-Henning Klusmann +25 more
TL;DR: The tumor-suppressive function of miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms.
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Novel pyrazolo[3,4-d]pyrimidines: design, synthesis, anticancer activity, dual EGFR/ErbB2 receptor tyrosine kinases inhibitory activity, effects on cell cycle profile and caspase-3-mediated apoptosis.
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References
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CA : A Cancer Journal for Clinicians
Patrizia Agostinis,Kristian Berg,Keith A. Cengel,Thomas H. Foster,Albert W. Girotti,Sandra O. Gollnick,Stephen M. Hahn,Michael R. Hamblin,Asta Juzeniene,David Kessel,Mladen Korbelik,Johan Moan,Pawel Mroz,Dominika Nowis,Jacques Piette,Brian C. Wilson,Jakub Golab +16 more
Journal ArticleDOI
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Susumu Kobayashi,Titus J. Boggon,Tajhal Dayaram,Pasi A. Jänne,Olivier Kocher,Matthew Meyerson,Bruce E. Johnson,Michael J. Eck,Daniel G. Tenen,Balazs Halmos,Balazs Halmos +10 more
TL;DR: In this paper, the authors reported the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission.
Journal ArticleDOI
STATs in cancer inflammation and immunity: a leading role for STAT3
TL;DR: Signal transducer and activator of transcription proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer, and STAT3 is a promising target to redirect inflammation for cancer therapy.