Overcoming Resistance to Kinase Inhibitors: The Paradigm of Chronic Myeloid Leukemia

Abstract

Sara De Santis,1 Cecilia Monaldi,1 Manuela Mancini,2 Samantha Bruno,1 Michele Cavo,1,2 Simona Soverini1 1Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, UO Ematologia ‘Lorenzo e Ariosto Seràgnoli’, Università di Bologna, Bologna, Italy; 2IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, ItalyCorrespondence: Sara De SantisInsitute of Hematology “Lorenzo e Ariosto Seràgnoli”, Via Massarenti 9, Bologna, 40138, ItalyTel [phone]Fax [phone]Email [email protected]: Protein kinases (PKs) play crucial roles in cellular proliferation and survival, hence their deregulation is a common event in the pathogenesis of solid and hematologic malignancies. Targeting PKs has been a promising strategy in cancer treatment, and there are now a variety of approved anticancer drugs targeting PKs. However, the phenomenon of resistance remains an obstacle to be addressed and overcoming resistance is a goal to be achieved. Chronic myeloid leukemia (CML) is the first as well as one of the best examples of a cancer that can be targeted by molecular therapy; hence, it can be used as a model disease for other cancers. This review aims to summarize up-to-date knowledge on the main mechanisms implicated in resistance to PK inhibitory therapies and to outline the main strategies that are being explored to overcome resistance. The importance of molecular diagnostics and disease monitoring in counteracting resistance will also be discussed.Keywords: protein kinases, chronic myeloid leukemia, tyrosine kinase inhibitors, synthetic lethality

Keywords

• protein kinases
• chronic myeloid leukemia
• tyrosine kinase inhibitors
• synthetic lethality.