Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 108
Targeting the cell cycle and the PI3K pathway: a universal strategy to reactivate innate
tumor suppressor programmes in cancer cells?
Thérèse David-Pfeuty1*, Michel Legraverend2 , Odile Ludwig2, and David S. Grierson2
Institut Curie-Recherche, 1UMR 146 and 2UMR 176 du CNRS, Bâtiment 110, Centre
Universitaire, 91405 Orsay Cedex, France
A rationale for why corruption of the Rb and p53 modules facilitates tumorigenesis is because
it lends oncogene-bearing cells a surfeit of Cdk activity and growth enabling them to
elaborate strategies to evade tumor suppressor mechanisms and inappropriately divide. Thus,
a potentially universal means to palliate their deficiency in cancer cells would be to target
both the activity of Cdks and their PI3K module that is a central regulator of cell growth. This
hypothesis is supported by our observation that the killing efficacy of Cdk inhibitors,
roscovitine and 16 other purine derivatives, decreased with increasing corruption of the Rb
and p53 modules. Notably, the two most resistant tumor cell lines were (Rb-/p53-) Saos-2,
followed by HBL100 (in which Rb and p53 are inactivated by binding to the large T antigen
of SV40); conversely, the most sensitive cell lines were (Rb+/p53*) HaCaT and A431 that
display normal differentiation features in culture, suggestive of a robust Rb pathway, followed
by (Rb+/p53+) MCF-7 and SCC15 tumor cell lines that carry a faulty Rb pathway. A further
case has been provided by the observation that the potentiation of roscovitine-induced
apoptosis by the PI3K inhibitor, LY294002, also decreased with increasing corruption of the
Rb and p53 modules. Another important finding of our work is that purines differing by a
single substitution, which exerted little lethal effects on distant cell types (differing by their
Rb/p53 status and tumorigenic potential) grown on a rich medium, could display widelydiffering
cytotoxicity profiles toward the same cell types grown on a poor medium. This
highlights that structurally related compounds targeting the same Cdks may also target unique
proteins or Cdks that may control unique biological functions or compete for the interaction
between the compounds and their therapeutically relevant Cdk targets. The range and
concentration of such crossreacting targets would depend on the cell translational capacity
that, in turn, would depend on the cell genotype. In the perspective of clinical development in
association with inhibitors of the PI3K pathway, it might be advised, then, to select tumor cell
type-selective Cdk inhibitors on the basis of their cytotoxicity in cell-based assays performed
at a limiting serum concentration, sufficient to suppress their interaction with undesirable
crossreacting targets.
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