Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies

Abstract

The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.

Figure 1

The Ras/MAPK signaling cascade and small molecule inhibition. Ras genes exist as a multigene family that encodes small GTPases. Ras is a critical signaling hub in the cell that is activated by receptor tyrosine kinases (RTK), G-protein-coupled receptors, cytokine receptors, and extracellular matrix receptors. Receptor activation recruits Growth factor receptor-bound protein 2 (Grb2), an adaptor protein, which recruits Son-of-sevenless homolog (SOS1) and Shp2 (the protein product of PTPN11, which encodes a non-receptor tyrosine phosphatase). Ras activation results in the activation of Raf (BRAF, CRAF, ARAF), the first MAPK kinase of the cascade. Raf phosphorylates and activates MEK (MEK1 and MEK2), which in turn phosphorylates and activates ERK (ERK1 and ERK2). Phosphorylated ERK is the ultimate effector of the MAPK cascade and exerts its function on several downstream molecules. Feedback loops (solid lines) exist within the pathway whereby activated ERK can inhibit at the level of the receptor, SOS and Raf. Potential therapeutics for CS (caused by heterozygous activating missense HRAS mutations) and CFC (caused by heterozygous mutations in BRAF, MEK1, or MEK2) include FTIs, BRAF inhibitors, and MEK inhibitors (dashed lines; Table II).