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of imatinib revealed that this targeted drug is most effective in controlling glucose
transport, direct glucose oxidation for RNA ribose synthesis in the pentose cycle, as
well as de novo long-chain fatty acid synthesis. Thus imatinib deprives transformed
cells of the key substrate of macromolecule synthesis, malignant cell proliferation,
and growth. Tracer-based MRS studies revealed a restitution of mitochondrial glu-
cose metabolism and an increased energy state by reversing the Warburg effect,
consistent with a subsequent decrease in anaerobic glycolysis. Recent in vitro
SIDMAP studies that involved myeloid cells isolated from patients who developed
resistance against imatinib indicated that non-oxidative ribose synthesis from glu-
cose and decreased mitochondrial glucose oxidation are reliable metabolic signa-
tures of drug resistance and disease progression. There is also evidence that
imatinib-resistant cells utilize alternate substrates for macromolecule synthesis to
overcome limited glucose transport controlled by imatinib. The main clinical impli-
cations involve early detection of imatinib resistance and the identifi cation of new
metabolic enzyme targets with the potential of overcoming drug resistance down-
stream of the various genetic and BCR-ABL-expression derived mechanisms.
Metabolic profi ling is an essential tool used to predict, clinically detect, and treat
targeted drug resistance. This need arises from the fact that targeted drugs are nar-
rowly conceived against genes and proteins but the metabolic network is inherently
complex and fl exible to activate alternative macromolecule synthesis pathways that
targeted drugs fail to control.
Management of Drug Resistance in Cancer
Chemogenomic Approach to Drug Resistance
Resistance to anticancer drugs represents a serious obstacle to successful cancer
treatment. Genome-wide studies correlating drug response phenotypes with large
DNA/tissue microarray and proteomic datasets have been performed to identify the
genes and proteins involved in chemosensitivity or drug resistance. The goal is to
identify a set of chemosensitivity and/or resistance genes for each drug that are
predictive of treatment response. Therefore, validated pharmacogenomic biomark-
ers offer the potential for the selection of optimal treatment regimens for individual
patients and for identifying novel therapeutic targets to overcome drug resistance.
Approximately 10 % of patients with chemotherapy-resistant bowel cancer that
has spread to other parts of the body respond to treatment with MAbs – cetuximab
or panitumumab. These drugs target the EGFR. However, not every CRC patient
responds well to this treatment. An understanding the molecular basis of clinical
sensitivity or resistance to anti-EGFR agents might identify patients who are likely
to benefi t from treatment with these MAbs. Those not likely to respond to MAb
treatment should be spared the expense and potential adverse effects.
KRAS mutations are associated with anti-EGFR resistance. In patients with
wild-type KRAS, the presence of BRAF mutation or PIK3CA mutations is
10 Personalized Therapy of Cancer