Page 9 - ITPS-7-1

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

3. Pharmacogenetics in cancer NSCLC, and it is the first KRAS inhibitor to reach the
market and enter clinical use .
[15]
The use of the molecular genetic methods that allows
early detection of clones harboring driver mutations has The example provided by the first experience with
achieved immediate and widespread in all aspects of clinical imatinib and BCR-ABL allowed the development and
oncology, allowing the identification of a large number of rapid clinical use of new inhibitors of these mutated kinases
mutations with pharmacological interest in most solid to block different intracellular signals of proliferation,
tumors. This also promotes the development of a wide immortality, and metastasis present in different types of
spectrum of new therapeutic molecules directed at each of tumors, such as breast cancer, NSCLC, colon carcinoma,
these genetic variants. Thus, this methodology allows early and melanoma. Many of these tumors proliferate at the
detection of tumor and enables informed decision-making expense of the stimulation produced by growth factors.
in the selection of specific therapies that can control tumor However, the same tumors can also proliferate without
growth, recurrence and metastatic progression. These the need for growth factor stimulation due to the presence
stratagems of selective therapies only act on somatically of activating mutations of the proteins of the signaling
mutated targets expressed in neoplastic cells, with no cascades responsible for tumor growth (Figure 2).
effect on normal cells. These developments ushered in The presence of sensitive mutations, which favor the
the new era of the so-called personalized therapies, and insertion of ITKs in the active ATP binding site in the
more recently “precision medicine” in cancer. The new ATPase pocket of the enzyme, is a therapeutic opportunity
anti-cancer medications known as “targeted therapies” that has significantly changed the prognosis and evolution
have emerged and aroused great interest in recent years. of different types of tumors. Furthermore, analysis
In this group of agents, there is a wide range of inhibitors of circulating tumor DNA profiling has also enabled
of different tyrosine kinases or serine/threonine kinases, tracking of clonal variations in patients with colorectal
which are purportedly responsible for motorizing tumor carcinoma, assisting the monitoring of tumor progression
growth, either by their stimulated (dependent) activation and therapeutic resistance against EGFR blockade in real
by extracellular growth factors, or by the presence time .
[18]
of somatic mutations that activate said kinases in an
independent manner on their corresponding growth factor. On the other hand, the presence of mutations in the
Several kinase inhibitors (KI) emerged as molecules with same gene but that modify its protein conformation,
a high capacity to penetrate the active site of the kinase, preventing the action of the corresponding ITKs mentioned
preventing ATP access to that site, and thus inhibiting its above, makes it necessary to look for new second-line
tyrosine kinase activity with concentration values at the ITKs specific for this type of mutation, such is the case of
picomolar level [11-13] . sensitive and resistant mutations present in the EGFR in
NSCLC. In these patients with NSCLC, a large number
The non-small cell lung cancer (NSCLC) affects almost of different sensitive mutations but a smaller number of
17% of Western patients that have an activating epidermal resistant mutations have been described [19,20] .
growth factor receptor (EGFR) gene mutation, with Del19
and L858R being the most common ones. These mutations To date, several EGFR tyrosine kinase inhibitors (TKIs)
are sensitive to ITK erlotinib (Tarceva; 60% response such as afatinib, erlotinib, gefitinib, and osimertinib
rate) or gefitinib (Iressa). However, a new clone carrying have already been approved for first-line treatment of
the drug-resistant EGFR T790M mutation emerges as a patients with advanced NSCLC harboring tumor growth
consequence of the pharmacological pressure exerted by driver mutations in EGFR gene. However, the correct
first-line ITK treatment. Although there are drugs that indication of these drugs requires the identification of
specifically inhibit the second mutation, clear evidence has the corresponding sensitive and/or resistant mutations
already emerged that various mechanisms of resistance in this gene . The most common sensitive mutations
[21]
activated by other or downstream signaling pathways, are deletions in exons 18, 19, and 21 (5%, 45%, and 45%
including RAS, RAF, and MAPK pathway . of cases, respectively). Meanwhile, among the resistant
[14]
Because the mutation of EGFR and KRAS are mutually mutations (5% of cases), the most frequent corresponds to
exclusive, detection of KRAS mutations in patients with the T790M mutation in exon 20, which can be treated with
non-mutated EGFR could provide insights into other a specific ITK as second-line therapy. However, whether a
therapeutic options. In this regard, recently, the U.S. Food significant number of mutations detected in EGFR gene are
[22]
and Drug Administration (FDA) has approved sotorasib pharmacologically actionable remains to be explored .
(AMG 510, Amgen), the covalent inhibitor on the more The presence of these mutations necessitates
common KRAS mutant (G12C), for the treatment of personalized therapy with the corresponding ITK, but the

Volume 7 Issue 1 (2024) 3 https://doi.org/10.36922/itps.1227