Targeting oncogenic Ras signaling in hematologic malignancies

Abstract

Ras proteins are critical nodes in cellular signaling that integrate inputs from activated cell surface receptors and other stimuli to modulate cell fate through a complex network of effector pathways. Oncogenic RAS mutations are found in ϳ 25% of human cancers and are highly prevalent in hematopoietic malignancies. Because of their structural and biochemical properties, oncogenic Ras proteins are exceedingly difficult targets for rational drug discovery, and no mechanismbased therapies exist for cancers with RAS mutations. This article reviews the properties of normal and oncogenic Ras proteins, the prevalence and likely pathogenic role of NRAS, KRAS, and NF1 mutations in hematopoietic malignancies, relevant animal models of these cancers, and implications for drug discovery. Because hematologic malignancies are experimentally tractable, they are especially valuable platforms for addressing the fundamental question of how to reverse the adverse biochemical output of oncogenic Ras in cancer. (Blood. 2012;120(17): 3397-3406) IntroductionAberrant signal transduction resulting in reduced dependence on growth factors and other extracellular stimuli for the survival and proliferation of malignant cells is an established "hallmark of cancer." 1 RAS genes encode a family of 21-kDa proteins that are central nodes in signaling networks that regulate cell fate in many tissue lineages. RAS genes are also the most common targets of dominant somatic mutations in human cancer. 2,3 The high prevalence of mutations in NRAS, KRAS, and molecules, such as CKIT, PTPN11, CBL, and BCR-ABL1, that interact with Ras biochemically strongly implicate aberrant Ras signaling as an important therapeutic target in these cancers. [4][5][6][7] In this review, we focus on the pathobiology of mutations in hematologic cancers involving the "core" Ras-GTPase activating protein (GAP) complex, which includes Ras itself, guanine nucleotide exchange factors, and GAPs. At this writing, mutations in NRAS, KRAS, and the NF1 tumor suppressor, which encodes a GAP called neurofibromin, 8 are strongly associated with myeloid malignancies. Increasing evidence also implicates these genes as "drivers" in lymphoid cancers with "high-risk" clinical features. No mechanism-based treatments exist for the ϳ 25% of human cancers with KRAS or NRAS mutations or for the growing number of malignancies showing NF1 inactivation, and we discuss potential therapeutic strategies for addressing the adverse biochemical consequences of aberrant Ras signaling. Structural and functional properties of the Ras GTPase switchRas proteins are signal switch molecules that regulate cell fates by cycling between active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)-bound conformations. 9 On ligand binding, molecules, such as Shc, Grb2, Gab2, and SHP-2, are recruited to growth factor receptors and these complexes activate Ras guanine nucleotide exchange factors (GEFs; Figure 1). 10 GEFs catalyze dissociation of guanine nucleotides from Ras, which is followed by ...

NRAS isoforms differentially affect downstream pathways, cell growth, and cell transformation

“…In fact, the different structures of the NRAS isoforms must be considered in the context of NRAS inhibitors. So far, direct and indirect targeting of the aberrantly activated RAS pathway has shown varying success in the clinic, which most likely is because of the complexity of RAS gene functions (22)(23)(24). However, as only amino acids 1-17 are shared among all five isoforms, pharmacologic approaches to specifically influence the expression of different isoforms (e.g., isoform 5 inhibition) might represent an option to enhance the effective targeting of this "undruggable" molecule (25).…”

The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer

“…RAS protein activity is tightly regulated by Guanine Nucleotide Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs). Constitutive activation of the RAS protein, in which RAS is unable to hydrolyze GTP, leads to cancer and other diseases [1,9,12] . Activating RAS mutations have been observed in 30% of human tumors [2,13] ; KRAS is the most commonly mutated isoform, mutated in 25%-30% of human cancers [3,13] .…”

“…Not coincidentally, increased activities of all of these processes are required by tumor cells to promote tumor growth. Activating oncogenic RAS mutations lead to treatment resistance in various tumor models and poor patient outcomes [3,[5][6][7][8][9] . Three human RAS genes have been identified: HRAS, KRAS, and NRAS [1,2] .…”

The mystery of oncogenicKRAS: Lessons from studying its wild-type counter part

“…1 The first 85 amino-terminal residues are identical and the middle 78 amino acids share an 85% -90% identity among all Ras isoforms, while the last 25 amino acids at the carboxyl-terminus are highly variable. 2 In haematopoietic neoplasms, oncogenic mutations in the NRAS and KRAS genes are common, but rare in the HRAS gene. 2 Despite the high similarity in protein sequences and largely overlapping expression patterns, accumulating evidence suggest that Kras G12D/C expressed from its endogenous locus demonstrates much stronger leukemogenic activity than oncogenic Nras alleles (including Nras G12D alleles) (Fig.…”

“…2 In haematopoietic neoplasms, oncogenic mutations in the NRAS and KRAS genes are common, but rare in the HRAS gene. 2 Despite the high similarity in protein sequences and largely overlapping expression patterns, accumulating evidence suggest that Kras G12D/C expressed from its endogenous locus demonstrates much stronger leukemogenic activity than oncogenic Nras alleles (including Nras G12D alleles) (Fig. 1).…”