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Systems Biology Approach to Drug Resistance in Colorectal Cancer
Mechanisms that may have important implications for drug effi cacy and actively
contribute to innate resistance in colorectal cancer (CRC) are:
- High levels of thymidylate synthase, the 5-FU target, are associated with tumor
insensitivity to FU-based therapy. - Higher levels of topoisomerase-I (TOP1) correlate with greater sensitivity of
colon tumors to camptothecin derivatives compared to normal colonic mucosa. - Glucuronidation, involved in xenobiotic detoxifi cation, is also associated with
innate resistance to TOP1 inhibitors in colon cell lines and tumors. - An increase of the ABCB1/P-gp transporter, a member of the family of ABC-
transporters that detect and eject anticancer drugs from cells, is observed in
intrinsically drug-resistant colon tumors.
In a systems biology approach to understand innate CRC tumor responses to a
FOLFIRI combined chemotherapy of irinotecan (CPT-11) plus 5-FU/FA, gene
expression patterns obtained with microarrays were compared between clinical
samples from colon tumors and liver metastases collected from CRC patients prior
to drug exposure (Grauden et al. 2006 ). Use of a vigilant experimental design,
power simulations and robust statistical analysis reduced the false negative and
positive differential hybridization rates to a minimum. Data collected from a bio-
logical systems perspective into global and interconnected molecular networks
highlight the molecular mechanisms that may anticipate resistance in CRC patients
prior to their exposure to drugs. This knowledge could be used in clinical practice
as a complement to clinical, biochemical and genetic biomarkers for global preven-
tion, early diagnosis and better patient treatment.
Resistance to Targeted EGFR Blockade in CRC
CRC that is wild type for KRAS is often sensitive to EGFR blockade, but almost
always develop resistance within several months of initiating therapy. This situation
is in marked contrast to that of small-molecule targeted agents, such as inhibitors of
ABL, EGFR, BRAF and MEK, in which mutations in the genes encoding the pro-
tein targets render the tumors resistant to the effects of the drugs. Two studies have
provided an explanation of why solid tumors develop resistance to targeted thera-
pies in a highly reproducible fashion and provide a basis for overcoming this. One
study of circulating tumor DNA found that 38 % patients whose tumors were ini-
tially KRAS wild type developed detectable mutations in KRAS in their sera and
some of them developed multiple different KRAS mutations (Diaz et al. 2012 ). The
appearance of these mutations was very consistent, generally occurring between 5
and 6 months following treatment. Mathematical modeling indicated that the muta-
tions were present in expanded subclones before the initiation of panitumumab
treatment. These results suggest that the emergence of KRAS mutations is a
10 Personalized Therapy of Cancer