The Bcl-2/Bax and Ras/Raf/MEK/ERK signaling pathways: implications in pediatric leukemia pathogenesis and new prospects for therapeutic approaches

Abstract

The Bcl-2/Bcl-xL/Bax and the Ras/Raf/MEK/ERK (MAPK) pathways are often deregulated in many human cancers and especially in acute lymphoblastic leukemia and acute myeloid leukemia. A result of molecular alterations of these pathways is uncontrolled cell growth and survival, ultimately resulting in oncogenic transformation and progression. Aberrant expression of Bcl-2/Bax and MAPK can lead to therapeutic resistance. In this review, the Bcl-2 and MAPK pathways are analyzed, focusing the attention on their molecular alterations, and the complex interactions between these signaling cascades are also analyzed. The observation that both MAPK and Bcl-2/Bax signaling play a central role in the pathogenesis of human cancer suggests that this kinase cascade represents a novel opportunity for the development of new anticancer targeted therapies designed to be less toxic than conventional chemotherapy. The evidence that they are often implicated in sensitivity and resistance to leukemia therapy suggests that characterization of the cancer genome may offer personalized cancer genomic information that can lead to the formulation of much more effective personalized therapy.

Keywords::

• Bcl-2/Bax
• leukemia
• MAPK
• MAPK and Bcl-2 pathway
• mutations

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • The Raf-mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) (MAPK) kinase (MEK)-ERK signal transduction cascade and members of the Bcl-2 family are frequently alterated in hematological malignancies such as acute myeloid leukemia (AML) and childhood acute lymphoblastic leukemia (ALL).

• • Ras/Raf/MEK/ERK (MAPK) and Bcl-2 family’s protein signaling pathway influence both progression and relapse in some patients.

• • Bcl-2 pathway and the Raf/MEK/ERK pathway are important pathways to target for therapeutic intervention.

• • The observation that the MAPK and the Bcl-2/Bax signaling pathways play a central role in pathogenesis of human cancer highlights this kinase cascade as a novel opportunity for the development of new anticancer-targeted therapies designed to be less toxic than conventional chemotherapy.

• • The evidence that these pathways are often implicated in sensitivity and resistance to leukemia therapy suggests that a characterization of the cancer genome might offer personalized cancer genomic information and can lead to the formulation of much more effective personalized therapy.

• • Recent advances have yielded both pan-Bcl-2 small molecule inhibitors (SMIs) that inhibit both the Bcl-2 and the Mcl-1 arm of the Bcl-2 family anti-apoptotic proteins, as well as selective SMIs to differentially target the two arms. Of these SMIs, ABT-263 (navitoclax), ABT-199, BI-97C1 (sabutoclax) and obatoclax (GX15–070) are currently in clinical trials for multiple cancers.

• • Several MEK inhibitors are in clinical trials; trametinib and selumetinib may represent a promising agent for the treatment of AML and ALL.