Gene mutations and molecularly targeted therapies in acute myeloid leukemia.

Acute myelogenous leukemia (AML) can progress quickly and without treatment can become fatal in a short period of time. However, over the last 30 years fine-tuning of therapeutics have increased the rates of remission and cure. Cytogenetics and mutational gene profiling, combined with the option of allogeneic hematopoietic stem cell transplantation offered in selected patients have further optimized AML treatment on a risk stratification basis in younger adults. However there is still an unmet medical need for effective therapies in AML since disease relapses in almost half of adult patients becoming refractory to salvage therapy. Improvements in the understanding of molecular biology of cancer and identification of recurrent mutations in AML provide opportunities to develop targeted therapies and improve the clinical outcome. In the spectrum of identified gene mutations, primarily targetable lesions are gain of function mutations of tyrosine kinases FLT3, JAK2 and cKIT for which specific, dual and multi-targeted small molecule inhibitors have been developed. A number of targeted compounds such as sorafenib, quizartinib, lestaurtinib, midostaurin, pacritinib, PLX3397 and CCT137690 are in clinical development. For loss-of-function gene mutations, which are mostly biomarkers of favorable prognosis, combined therapeutic approaches can maximize the therapeutic efficacy of conventional therapy. Apart from mutated gene products, proteins aberrantly overexpressed in AML appear to be clinically significant therapeutic targets. Such a molecule for which targeted inhibitors are currently in clinical development is PLK1. We review characteristic gene mutations, discuss their biological functions and clinical significance and present small molecule compounds in clinical development, which are expected to have a role in treating AML subtypes with characteristic molecular alterations.