275associated with lower disease control rate, shorter progression-free survival, and
shorter overall survival. MET overexpression, in addition to BRAF and PIK3CA
mutations, is a predictive biomarker for responsiveness to anti-EGFR MAbs in
mCRC patients with wild-type KRAS (Kishiki et al. 2014 ). In patients with KRAS
mutations, those with high levels of hepatocyte growth factor (HGF) or epiregulin
(EREG) have shorter progression-free survival and overall survival compared with
those with low levels of HGF or EREG (Takahashi et al. 2014 ). One study has
explored miRNAs as biomarkers of response to anti-EGFR MAbs and found that
MiR-99a/Let-7c/miR-125b signature may improve the selection of patients with
KRAS wild-type mCRC as good candidates for this therapy (Cappuzzo et al. 2014 ).
Determination of Chemotherapy Response by Topoisomerase Levels
Topoisomerase poisons are chemotherapeutic agents that are used extensively for
treating human malignancies. These drugs can be highly effective, yet tumors are
frequently refractory to treatment or become resistant upon tumor relapse. Top2A
expression levels are major determinants of response to the topoisomerase-2 poison
doxorubicin and suppression of Top2A produces resistance to doxorubicin.
Suppression of Top1 produces resistance to the topoisomerase 1 poison camptoth-
ecin but hypersensitizes cancer cells to doxorubicin. Lymphomas relapsing after
treatment display spontaneous changes in topoisomerase levels as predicted by
in vitro gene knockdown studies using RNAi screens in animal models of cancer.
Thus pooled shRNA screens can be used for identifying genetic determinants (bio-
markers) of chemotherapy response and improve the effectiveness of topoisomerase
poisons in the clinic (Burgess et al. 2008 ).
Management of Drug Resistance in Leukemia
Imatinib mesylate (Novartis’ Gleevec), approved in 2001, causes remission in
patients with chronic myeloid leukemia (CML). Despite these positive response
rates, a subset of patients do not respond to Gleevec therapy fully or at all, and
approximately 4–5 % of successfully treated patients annually develop resistance to
Gleevec during therapy with a return of their disease manifestations. The molecular
hallmark of CML is a mutation known as BCR-ABL. This mutation is the specifi c
target for Gleevec and is found in 95 % of patients with CML. Secondary mutations
in the ABL portion of the gene correlate with treatment failure or relapse in most
patients on Gleevec therapy. Genzyme has licensed exclusive worldwide diagnostic
rights from the University of California (Los Angeles, CA) Jonsson Cancer Center
to its discovery of gene mutations believed to be associated with drug resistance to
Gleevec. Genzyme will be the fi rst company to develop and market a diagnostic test
to detect a signifi cant portion of these secondary BCR-ABL mutations and monitor
resistance in CML patients prior to and during treatment with Gleevec. Results from
such a test may assist physicians in predicting patient relapse before it happens and
making appropriate adjustments in treatment.
Therapy Resistance in Cancer