A személyre szabott terápia legújabb lehetőségei a molekuláris onkológiában
Authors: Menyhárt Otília , Vas Virag , Győrffy Balázs , Buday László 
Published: October 2021

Összefoglaló. A molekuláris onkológia térnyerésével számos új
lehetőség érhető el a daganatos betegek hatékonyabb kezelésére. Ilyen a klinikai
vizsgálatokban alkalmazott, a valóban személyre szabott kezelést elősegítő
génpanelelemzés, illetve a célzott kezelés szövettípustól független alkalmazása.
A személyre szabott terápiák jelentős hányada valamelyik kinázt gátolja. Az
összefoglalónkban bemutatjuk a RAS jelátviteli út sejten belüli komplex
szabályozását, valamint ismertetjük az útvonal további farmakológiai szempontból
kiaknázható célpontjait nemzetközi és saját eredményeink alapján. A kinázokat
érintő gyakori mutációk ellenére számos daganattípusban nem áll rendelkezésre
személyre szabott terápia. A hagyományos terápiával nem kezelhető agydaganatok
példáján keresztül bemutatjuk a tirozin-kinázok várható jövőbeli terápiás
jelentőségét.

Summary. With the advent of molecular oncology, the identification
of mutations in solid tumours is now clinically routine. The growing repertoire
of targeted therapeutic agents has supported the rise of a new type of clinical
trial in which the selection of the therapeutic agent is no longer restricted to
a single option. Instead, a panel of genes is screened to identify the most
suitable drug for each patient. Such trials have delivered objective response
rates in 5–30% of patients. Most of the signal transduction pathways targeted by
these agents involves RAS signaling.

Somatic mutations in RAS genes are common in human tumours. Such mutations
generally decrease the ability of RAS to hydrolyze GTP, maintaining the protein
in a constitutively active GTP-bound form that drives uncontrolled cell
proliferation. Recent emerging data suggest that RAS regulation is more complex
than the scientific community has appreciated for decades. We discuss a novel
type of RAS regulation that involves direct phosphorylation and
dephosphorylation of RAS tyrosine residues. The discovery that pharmacological
inhibition of the tyrosine phosphoprotein phosphatase SHP2 maintains mutant Ras
in an inactive state suggests that SHP2 could be a novel drug target for the
treatment of Ras-driven human cancers.

In addition to RAS gene mutations, other common oncogenic events have also been
identified, including mutation of EGFR (epidermal growth factor receptor) or
BRAF (isoform B of rapidly accelerated fibrosarcoma). EGFR has tyrosine kinase
activity while BRAF acts as a serine/threonine kinase. In some tumours, mutant
forms of these kinases over-activate cell proliferation, leading to uncontrolled
tumour cell growth; therefore, it seems rational to develop inhibitor molecules
that target these hyper-active oncogenic kinases to reduce tumour cell burden in
cancer patients.

Fusion protein kinases activated via the RAS pathway represent target proteins
with high clinical success rates. Recently approved TRK fusion protein kinase
inhibitors have reached response rates in almost 80% of patients regardless of
tumour type. Although these drugs can only be administered to patients whose
tumours harbour a TRK fusion protein, such success stories pave the way for
future development of agents that target similar genetic mutations.

Glioblastoma multiforme, a relatively frequent, almost uniformly fatal brain
tumour, has ubiquitous alterations in tyrosine-kinase signalling. Nevertheless,
to this day, no tyrosine-kinase inhibitors have been approved for its treatment.
We have ongoing research projects to uncover associations between initial gene
expression levels in untreated glioblastoma samples and treatment-related
survival, and we have identified overexpression of druggable tyrosine-kinase
receptors in chemotherapy-resistant patients. Our approach will help to identify
patients who might benefit from concurrent use of tyrosine kinase inhibitors and
conventional cytotoxic therapies.