PEBC Report - Programa de Epigenética y Biología del Cáncer

goal, it will be necessary to expand the repertoire of druggable
targets beyond those actually mutated in the tumor by
including other targets within the same pathways, providing
that their inhibition will have similar consequences.
An illustrative example of such tumors are those carrying
mutations in the K-Ras oncogene. These tumors account
for about one third of all human malignancies, including
those with rather poor outcomes such as pancreatic adenocarcinoma
(PDA), colorectal carcinoma (CRC) and nonsmall
cell lung carcinoma (NSCLC). Unfortunately, the K-Ras
oncoprotein is not druggable since this molecule owes its
tumorigenic properties to mutations that eliminate its intrinsic
enzymatic activity (a GTPase). Hence, there are no available
strategies to block K-Ras oncogenic signaling. On the
hand, Ras signaling pathways are loaded with druggable
kinases some of which (B-Raf, PI3K, Akt) have also been
found mutated in other human tumors. Thus, it could be
argued that blocking one of these downstream kinases
should have significant therapeutic effect. Unfortunately,
early clinical results, at least with B-Raf inhibitors, have not
been too encouraging.
In order to understand the molecular bases of tumor intervention
in vivo and to devise better strategies to block oncogenic
signaling, we and others have developed mouse
tumor models in which an endogenous K-Ras oncogene
can be activated by genetic means in adult animals leading
to the development of tumors that faithfully resemble those
observed in human patients. These mice can be subsequently
endowed with germ line, or better, conditional mutations
whose activation ablates the putative therapeutic targets.
These mice can be used to evaluate the relative contribution
of these targets to tumor development by eliminating
them, either alone or in combination, at various times
during tumor progression. I will present our most recent
results following these basic strategies to evaluate the therapeutic
effect of ablating the Raf, Mek and Erk kinases as
well as the cell cycle Cdks (Cdk2, Cdk4 and Cdk6) in K-Ras
induced NSCLCs.
Cancer Epigenetics and Biology Symposium
16 28, 29 May 2009, Barcelona