**8. Conclusions**

*Advances in Precision Medicine Oncology*

special characteristic that is missing in nearly all the other forms of malignancy. Indeed, conversely from other cancers, in which each genotype encodes diverse phenotypic traits, CML displays an unambiguous genotype–phenotype relationship. However, although most of patients responded excellently to Imatinib therapy a minority relapsed. Especially those patients with advanced CML phases initially respond to Imatinib but then progressed to accelerated or blast crisis. The reason for the relapse is straightforward: while in the patients that respond to Imatinib the BCR-ABL tyrosine kinase activity is abrogated, in those that relapse the tyrosine kinase is reactivated due to mechanisms that either prevent Imatinib to reach the target or render the target insensitive to Imatinib. A combination of approaches, including functional studies that have been then validated by the crystallization of the ABL tyrosine kinase domain with Imatinib coupled with the sequencing of the ABL tyrosine kinase domain, allowed to identify and determine critical contact points between the protein and the inhibitor [68, 69]. Indeed, most of the patients who developed Imatinib insensitivity harbor ABL tyrosine kinase point mutation, especially in the P-loop decreasing its flexibility and therefore its capability to bind to Imatinib. The resistance to Imatinib has led to the development of second generation of tyrosine kinase inhibitors (Nilotinib™, Dasatinib™ and Bosutinib™) and the boost of pharmacogenomics [70]. Imatinib is effective also in the treatment of various malignancies, other than CML. For example, it has shown significant activity in patients with Acute Lymphoblastic Leukemia Ph + (ALL Ph+) [71], in a significant proportion of people with Gastrointestinal Tumor (GIST) that harbor c-KIT mutations [72] and those disorders characterized by translocations involving the PDGFRB gene, including myeloproliferative and myelodysplastic syndromes [73, 74]. The demonstration that small molecule inhibitors could effectively treat chronic myeloid leukemia opened the door to the development of new tyrosine kinase inhibitors and to the blooming era of targeted cancer therapies (**Figure 3**). Though cancer is the predominant indication for tyrosine kinase inhibitors (TKIs), currently the disease targets are extensively growing. For example, Tofacitinib™ is a Jak3 inhibitor that is currently approved for the treatment of rheumatoid arthritis [75, 76] and Nintedanib™ is a FGFR/multikinase inhibitor that is approved for the treatment of pulmonary fibrosis [77]. Furthermore, Pegaptanib, Ranibizumab and Aflibercept that act by inhibiting the VEGF receptor tyrosine kinase activity are currently used for the treatment of the age-related

*The FDA approval timeline of tyrosine kinase inhibitors (TKIs): Upon the approval of the Imatinib for the treatment of CML other TKIs have been developed and nowadays small molecules TKIs are dozens. Though, originally they have been designed for neoplasms in the last decade we have also witnessed to an amazingly* 

*growth of the diseases, other than cancers, that significantly benefit from TKIs treatment.*

**240**

**Figure 3.**

Advances in our understanding in tumor biology have encouraged not only the reassessment of the tumors classification by the site of origin in favor of molecular alterations but also in terms of oncogenic drivers (e.g. tyrosine kinases) amenable for treatment. Since Imatinib has been approved by FDA in 2001 as small molecule competing with ATP, dozens of orally effective small molecule protein kinase inhibitors have been subsequently approved. This is also due to the significantly shortening of the timelines of drug development, as it happened in the case of a record time for the Crizotinib™. The approval of Imatinib for the successful treatment of leukemia (CML) definitively chased away the notion targeting the ATPbinding sites of protein kinases was not selective or efficacious because of the large number of protein kinases, thus leading to copious side effects.
