RAS-MPAK Pathway Signaling in Health and Disease

Abstract The p21ras (Ras) family of signal switch molecules is an essential component of proliferative responses to many extracellular stimuli including most hematopoietic growth factors and cytokines. Phosphorylation of tyrosine residues on activated cytokine/growth factor receptors triggers multiple signaling pathways including JAK/STAT, Ras and PI3K. Activated Ras proteins further activate downstream effectors such as RAF/MEK/ERK, PI3K and RalGDS. Point mutations of Ras proteins are commonly found in human cancers and are estimated to occur in about 30% of cancer cases. These mutations lock Ras in the constitutively active conformation. In addition to point mutations of RAS, other genetic lesions such as the BCR-ABL fusion, PTPN11 mutations, FLT3 internal tandem duplications, CBL mutations and NF1 inactivation all lead to hyperactive Ras signaling. Besides cancers, RAS and Ras-activating mutations have been found in RASopathies, such as Neurofibromatosis type 1 (NF1), Noonan Syndrome, Costello syndrome, and Cardiofaciocutaneous syndrome (CFC). RAS mutations are highly prevalent in hematologic malignancies including chronic and juvenile myelomonocytic leukemia (CMML and JMML), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and multiple myeloma (MM). In contrast to epithelial cancers where KRAS mutations are highly prevalent, most mutations found in hematologic malignancies alter NRAS. Human genetic data and results from genetic mouse models support the idea that deregulated Ras signaling is initiating event in myeloproliferative neoplasms (MPNs) and MPN/MDS overlapping diseases. RAS mutations are detected among the initiating mutations in many cases of CMML and JMML, and can persist in patients who have achieved remission either spontaneously or after treatment. Furthermore, mutations of Nras and Kras, as well as leukemia-associated mutations that result in hyperactive Ras such as BCR-ABL, loss of NF1, PTPN11 or CBL mutations all induce MPN or MPN/MDS overlapping disease in mouse models. Although in adult de novo AMLs, human genetic data support a model in which RAS and Ras-activation mutations are likely secondary event, recent large scale next generation sequencing studies show that RAS and Ras-activating mutations are much more commonly found in pediatric than adult AML cases, and pediatric AMLs in general lack "adult pre-leukemic mutation' such as TET2, DNMAT3 or IDH1/2. These results suggest a possibility that RAS mutations can be initiating mutations in pediatric AMLs. In addition, even in AMLs where RAS mutations are secondary event, hyperactive Ras promotes leukemic stem cell self-renewal and is critical for leukemia maintenance, underscoring the importance of targeting Ras for leukemia treatment. Targeting Ras proteins remains to be challenging and significant ongoing effort focuses on developing direct inhibitors of Ras. In recent years, small molecules that bind to Ras proteins to prevent GEF-mediated GDP/GTP exchange, or target the RasG12C mutant allele, showed promising pre-clinical results. Besides, targeting Ras effectors, such as MEK/ERK, individually or in combination with other pathways, remains as a valid approach to halt Ras-induced malignant proliferation. Better understanding of the subcellular localization, feedback regulation and redundancy of Ras-activated signaling network under physiological and pathological contexts will shed light on developing new strategies to effectively attack Ras-driven cancers. Disclosures No relevant conflicts of interest to declare.