Title:Resistance of Cancer Cells to Targeted Therapies Through the Activation of Compensating Signaling Loops
VOLUME: 8 ISSUE: 3
Author(s):Viktoria von Manstein, Chul Min Yang, Diane Richter, Natalia Delis, Vida Vafaizadeh and Bernd Groner
Affiliation:Georg Speyer Haus, Institute for Biomedical Research, Paul Ehrlich Str. 42, D-60596 Frankfurt am Main, Germany.
Keywords:Drug resistance, signaling redundancy and compensation, targeted tumor therapy.
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 PStat5
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.
