On-target side effects of the target therapies

Tímár József (1), Uhlyarik Andrea (2)
(1) Semmelweis Egyetem, Patológiai, Igazságügyi és Biztosításorvostani Intézet, Budapest
(2) Semmelweis Egyetem Belgyógyászati és Onkológiai Klinika, Budapest

Target therapeutics, aspecially the „first generation ones” target key proteins of the tumors which are expressed by normal cells or can be selective for mutant proteins (meaning that they affect normal version as well), accordingly, target therapies have unique side-effect profiles called on-target ones. Angiogenesis inhibitors affect VEGF-mediated physiological processes, such as hemostasis, wound healing or blood pressure. Bone-metastasis drugs induce side effects due to osteoclast suppression in bone regeneration. HER-2 receptor is crucial in regeneration of the myocardium, accordingly anti-HER-2 agents can be cardiotoxic. EGFR is crucial in the continuous regeneration of multilayered epithelia, accordingly anti-EGFR agents induce dermatitis. Multikinase inhibitors are „durthy drugs” and most of them have KIT inhibitory activity, in this way target bone marrow and melanocytes, where this receptor plays a crucial role. In case of TRK inhibitors neurons became target as well since NRTK is a key regulator of these cell types. Even mutant BRAF inhibitors develop unique side effects by reactivating RAS-RAF-MEK pathway, aspecially when RAS is mutated. Lipid kinase pathway inhibitors (PI3K, AKT or mTOR) are characterized by characteristic side effects, such as hyperglykemia or hyperlipidemia. Immune checkpoints are crucial regulators of the physiological immune homeostasis and the blockers acting on those targets, not only improve the antitumor efficacy of the immune reactions but in parallel may induce (re)activation of suppressed autoimmune processes.

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