PIM kinase family members have been implicated as important factors in the progression
and prognosis of various malignancies, including leukemia, breast, and prostate cancer.
As a result, PIM kinases are emerging as potential targe ts for solid tumors. In fact,
many pharmacological inhibitors of PIM kinases are already under clinical trials [1].
A growing body of evidence suggests that PIM kinases are particularly important in
the context of cellular stress, such as hypoxia. Notably, PIM kinase expression is
increased in hypoxia in a HIF-1- independent manner, which makes PIM inhibition a
novel approach to target the hypoxic tumor microenvironment. Recent reports highlight
hypoxia-induced PIM kinase expression as a novel signal transduction pathway that
provides protection against hypoxic stress by promoting survival and angiogenesis
(Figure 1) [2,3].
Figure 1
PIM kinase promotes survival and angiogenesis in response to hypoxia
Resistance to anti-angiogenic therapy is often attributed to the ability of hypoxic
cells to maintain a proliferative phenotype [4] and initiate angiogenic compensation
[5]. Casillas et al. tested the hypothesis that PIM kinase could be responsible for
imparting de novo and/or acquired resistance to anti-angiogenic agents, as these drugs
are designed to disrupt vasculature, which increases hypoxic stress [3]. Treatment
with anti-VEGF targeting agents dramatically increases PIM kinase expression, and
overexpression of PIM1 effectively blocks the ability of these drugs to prune tumor
vasculature. Moreover, PIM inhibitors dramatically reduce tumor vasculature when combined
with anti-VEGF therapies, suggesting that PIM is driving angiogenesis through a novel
VEGF-independent mechanism [3]. While PIM1 is not a HIF-1 target, it appears to be
an important signal for controlling the magnitude of HIF-1 signaling. PIM inhibitors
significantly reduce HIF-1 activation via promoting the hydroxylation-dependent degradation
of HIF-1. Thus, overexpression of PIM1, which is frequently observed in many solid
tumors, regardless of hypoxia, could inhibit the canonical HIF-1 degradation pathway,
representing a novel mechanism to explain the constitutive activation of HIF-1 observed
in cancer.
In addition to synergistic inhibition of tumor vasculature, combined inhibition of
PIM and VEGF results in enhanced cell death and a dramatic reduction in tumor cell
proliferation. The expression and activation of PIM kinase during hypoxia increases
the level of cytoprotective genes via Nrf2, which provides protection against reactive
oxygen species (ROS)-mediated cell death [2]. Studies conducted human subjects and
animal models have linked oxidative stress, ROS, and Nrf2 activation to numerous biological
functions, including survival and proliferation. Nrf2 provides protection from insults
such as xenobiotics and oxidative stress through activation of the cellular antioxidant
response by enhancing the expression of multiple genes combating free radical-associated
damage [6]. As a result, PIM indirectly regulates Nrf2 functions that promote survival
in hypoxia, such as cellular redox homeostasis, NADPH generation, autophagy, apoptosis,
and metabolism (heme, lipid, and glucose). Thus, targeting PIM kinases in cancer represents
a suitable approach to regulate Nrf2 activation, which might create better avenues
for combinatorial therapy to counteract drug resistance. Furthermore, PIM expression
has been implicated in the metastatic spread of prostate cancer [7]. PIM inhibitors
alone significantly reduce metastasis in orthotopic models of prostate and colon cancer
[3], indicative of a potential role for PIM in promoting the invasive phenotype associated
with hypoxia. Taken together, these findings demonstrate the breadth of cellular processes
that PIM kinases impact and provide further evidence of their importance as drivers
of therapeutic resistance in response to hypoxia.
In recent years, appreciation for the importance of the tumor microenvironment in
driving resistance to standard and targeted cancer therapies has grown considerably.
It is clear that in order to successfully treat solid tumors, we must target both
genetic and environmental factors that allow tumor cells to evade therapy and progress
to metastatic disease. PIM kinases are emerging as a critical, selective, and druggable
target to oppose hypoxia-mediated therapeutic resistance in cancer. Considering that
PIM inhibitors are actively being pursued in clinical trials, surprisingly little
is known about how the expression and activity of these kinases are regulated. Thus,
further efforts are warranted to understand how PIM kinases influence (and are influenced
by) the tumor microenvironment, as well as their multifaceted role in promoting the
aggressive, resistant phenotype associated with tumor hypoxia. A better understanding
of how PIM kinase expression and activity are controlled in hypoxia to propagate hypoxic
signaling will undoubtedly provide new and effective contexts in which PIM inhibitors
might overcome therapeutic resistance in solid tumors.