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Role of Splice Variants in Resistance to Cancer Therapy
Alternative splicing is important for increasing the diversity of the cellular proteome,
and is a process frequently deregulated during cancer development and progression.
In cancer cells, diverse splicing alterations have been identifi ed that eliminate pro-
tein domains or enzymatic activities required for effi cacy of cancer therapies, pro-
mote gain of novel signaling functions that circumvent cancer therapies, and
uncouple signaling pathways from upstream regulatory points that are blocked by
cancer therapies. The mechanisms underlying these splicing changes range from
stable alterations in gene sequence/structure to deregulation of splicing regulatory
factors. An understanding of these processes is leading to the development of novel
strategies for therapy re-sensitization (Dehm 2013 ).
Expression of P-Glycoprotein Gene by Tumor
The mechanism underlying multidrug resistance is a cellular pump called
P-glycoprotein, which normally protects cells from toxic substances by actively
exporting the offending compounds. In cancer, abundant P-glycoprotein gene
(MDR-1) expression by a tumor has been implicated as one of the major reasons
that cancer cells develop resistance to chemotherapy. Overexpression of MDR-1 in
tumors has been associated with resistance to adriamycin, paclitaxel, and many
more anticancer drugs. A simple DNA test has been devised by Epidauros
Biotechnologie AG that enables a physician to predict drug uptake from the begin-
ning of therapy of cancer and avoid the trial and error approach. This test for detec-
tion of gene polymorphisms is based on the knowledge that MDR-1 has 15
polymorphisms of which only one correlates with poor drug uptake.
Overexpression of Multidrug Resistance Gene
Approximately 75 % of cancer patients are intrinsically unresponsive or develop
resistance to anticancer drugs. The mechanism underlying multidrug resistance
(MDR) is a cellular pump called P-glycoprotein. Under normal circumstances,
P-glycoprotein protects cells from toxic substances by actively exporting the offend-
ing compounds. In cancer, abundant P-glycoprotein gene (MDR-1) expression by a
tumor has been implicated as one of the major reasons that cancer cells develop
resistance to chemotherapy. Overexpression of MDR-1 in tumors has been associ-
ated with resistance to adriamycin, paclitaxel, and many more anticancer drugs.
A simple DNA test has been devised by Epidauros Biotechnology that enables a
physician to predict drug uptake from the beginning of therapy of cancer and avoid
the trial and error approach. This test for detection of gene polymorphisms is based
on the knowledge that MDR-1 has 15 polymorphisms of which only one correlates
with poor drug uptake. Once detected, management of drug-resistance is still
10 Personalized Therapy of Cancer