Page 8 - ITPS-7-1

INNOSC Theranostics and
Pharmacological Sciences Liquid biopsy and digital PCR in cancer

against different therapeutic targets. There are specific administration of drugs directed exclusively against the
resistance mechanisms for each type of drug, which mutated proteins, responsible for tumor proliferation,
presupposes the possibility that such resistance can be has meant an extraordinary advance in the therapy of
avoided simply by changing the drug to be administered. neoplasia.
However, this first drug can often induce the expression The pioneer in this new field of pharmacology was
of this powerful ABC-t system, and consequently, the the advent of imatinib, an inhibitor of the tyrosine kinase
cancer cell will later reject any other therapeutic agent, (ITK) activity of the BCR-ABL fusion protein in chronic
and even combinations of several drugs administered myeloid leukemia (CML), which contributes to an overall
simultaneously. Interestingly, these patients will be “non- survival of 93% . However, as a consequence of the
[2]
responders” not only to the recommended doses, but even pharmacological pressure exerted, new neoplastic clones
to high doses, constituting the classic cases that we call with genetic variants resistant to said initial therapy may
“drug-resistant.” Unfortunately, these high doses will be emerge. This concept is applicable to all the molecules
ineffective for tumor treatment, and engender toxic effects introduced into the therapeutic arsenal of targeted drugs.
on other tissues, forcing the suspension of the medication. Consequently, the molecular identification of these
The discovery of this powerful multidrug drug resistance resistant-mutations, could allow alternative therapeutic
system is due to the pioneering work of Ropert Juliano and strategies directed towards these new genetic variants.
Victor Ling in the late 1970s (Figure 1).
[1]
In this regard, despite the very high percentages of
2. First pharmacogenetics-based detection remission achieved with this therapy in CML, it did not
of driver’s mutations of tumor growth take long for a minority number of non-responders to
arise, due to different mechanisms. Among them are the
In recent decades, the development of new molecular presence of ABC-t and the increase in the expression
methodologies has allowed the detection and of BCR-ABL by leukemic cells, which necessitate
characterization of the genetic profile of most tumors with administration of staggering doses culminating with only
high precision and specificity, as well as in a personalized suboptimal therapeutic responses , and the appearance
[3]
way for each affected individual. In such a way, this of cell clones with mutations in the BCR-ABL protein,
information makes it possible to identify the presence of which prevent the imatinib from taking effect and keep the
somatic mutations that drive the proliferation of tumor activated tyrosine kinase intact .
[4]
cells, and many of the mutations are pharmacologically
actionable. This new theranostic reality is a gigantic Perhaps, the best example of how important this new
breakthrough to overcome the multidrug-resistance modality of mutation detection and specific drug therapy
mechanism described in the above. In this way, the is clearly described in CML. The appearance of different
imatinib-resistant mutations in the BCR-ABL gene
(L248V, F317L, G250E, H396R, M244V, T277A, F311I,
M318T, Q252H, F359A, F359I, or Y326H) can be inhibited
with second- and third-generation of ITKs drugs, such as
dasatinib, nilotinib, and bosutinib . Furthermore, the
[5]
T315I mutation that confers resistance to imatinib and the
second- and third-generation ITKs is sensitive to another
ITK called ponatinib, allowing for the drug resistance in
this leukemia to be overcome, and prolonging survival of
the patients . In addition, polymorphisms in the MDR-1/
[6]
ABCB1 gene, such as C3435T, may favor the overexpression
of the transporter , which is associated with the poor
[7]
[8]
prognosis with imatinib in CML .
All these mechanisms are not mutually exclusive and
Figure 1. ATP-binding cassette transporters related to multidrug- can simultaneously contribute to therapeutic failure
resistance phenotype, such as P-glycoprotein (P-gp), breast cancer with ITKs. More recently, the possible concomitance
resistance protein, and multidrug resistance-associated proteins (MRPs), of mutations in the JAK2 gene has been suggested,
form an active ATP- and Ca -dependent drug pumping system, which capable of activating the BCR-ABL clone, even under the
2+
is capable of expelling a broad spectrum of substances (including drugs pharmacological pressure of the corresponding ITK, and
with different structures and directed to different targets) from the
interior to the exterior of the cells, preventing the access of the drugs to which requires the co-administration of a second ITK
their therapeutic targets. specific for JAK2 [9,10] .

Volume 7 Issue 1 (2024) 2 https://doi.org/10.36922/itps.1227