271coding genes specifi c to each breast cancer metastasis. The identifi ed signaling net-
works for the three types of breast cancer metastases contain 31, 15, and 18 proteins
and were used to reposition drug candidates for the brain, lung, and bone metasta-
ses. Both in vitro and in vivo preclinical experiments were conducted as well as
analysis on patient tumor specimens to evaluate the targets and repositioned drugs.
FDA-approved drugs, sunitinib and dasatinib, were found to inhibit brain metasta-
ses derived from breast cancer.
Therapy Resistance in Cancer
Human cancers are mostly found to be resistant to therapy at the time of drug pre-
sentation (primary responses), tumors being intrinsically drug resistant (innate or de
novo drug resistance). Only a few become resistant after an initial response (acquired
responses), the tumors developing resistance to chemotherapy during treatment
(acquired drug resistance). In the latter group, a tumor cell may express drug resis-
tance by combining several distinct mechanisms induced by its exposure to various
drugs. In the former group, however, this is unlikely to be the case.
Mechanism of Therapy Resistance in Cancer
One explanation of development of resistance is that when cells become cancerous,
they also become 100 times more likely to genetically mutate than regular cells.
Mutations protect cancer cells from therapeutics designed to target a particular
oncogene. A single tumor may have cells with many different types of oncogenes
and drug-resistant genes. Molecular diagnostics will help determine the stage and
malignancy of a tumor by testing the number of its mutations. The more mutations,
the further along the tumor may be in its development to malignancy or metastasis.
Resistance to drugs that shut down oncoprotein-driven pathways can occur because
of compensatory changes in connecting pathways. Loss of expression of MED12,
which acts in the TGFβ signaling pathway, may mediate resistance to gefi tinib and
vemurafenib (Rosell 2013 ).
Pharmacogenetics and pharmacogenomics studies of the relationship between
individual variations and drug response rates reveal that genetic polymorphisms of
specifi c genes is associated with clinical outcomes in patients treated through che-
motherapy, and amplifi cation of genes encoding drug targets or transporters alters
the sensitivity of cancer cells to a particular chemotherapy. Loss of heterozygosity
(LOH) at specifi c regions of chromosomes has been identifi ed in specifi c cancers
but its effect on treatment outcome remains controversial.
Therapy Resistance in Cancer