RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives

Abstract

NRAS and KRAS activating point mutations are present in 10-30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.

Fig. 1. Prevalence of NRAS and KRAS mutations in myeloid malignancies.

Percentage of mutated cases based on recent studies using high-throughput sequencing technologies and covering the entire N/KRAS coding sequence. AML: 1105 patients [12, 16]; MDS: 2957 patients [15]; CMML: 1540 patients (399 patients [15] and 1141 patients from unpublished personal data; JMML: 117 patients [13, 14, 17]. AML acute myeloid leukemia, MDS myelodysplastic syndromes, CMML chronic myelomonocytic leukemia, JMML juvenile myelomonocytic leukemia.

Fig. 2. Distribution of NRAS and KRAS mutation type in myeloid malignancies.

Distribution of the most frequently mutated codons in CMML (n = 1540), AML (n = 1105), JMML (n = 117) and MDS (n = 2975). The color code of each hotspot mutation is indicated on the right of each pie chart. The data are derived from the same patient cohorts as in Fig. 1.

Fig. 3. Recapitulative figure highlighting novel and ongoing therapeutic strategies for targeting RAS.

The binding of growth factors to the tyrosine kinase receptor leads to its phosphorylation and the binding to the Grb2/Sos complex. RAS is controlled by a loop of an inactive, GDP-bound state and an active, GTP-bound state. Activation of RAS occurs by the binding Guanine Nucleotide Exchange Factor (GEF) proteins, including SOS, which initiate the exchange of GDP for GTP. The GTP-bound RAS activates a cascade mechanism of downstream signaling molecules including RAF and PI3K, which regulates different cellular functions such as cell proliferation, differentiation, and cell growth/survival. This figure summarizes the druggable pathways and targets in clinical trials or that are potential therapies for future use. Four critical therapeutic axes are highlighted: direct RAS inhibitors, MEK inhibitors, PI3K inhibitors and PLK1 inhibitors. Targets labeled in green are those currently in clinical trials in hematologic diseases. Targets labeled in blue are FDA-approved in the oncology field. Preclinical and clinical drugs targeting RAS-mutant in solid tumors are labeled respectively in black and red. RTK receptor tyrosine kinase, PROTACs proteolysis-targeting chimeras, siRNA small interfering RNA.