Collectively, the results of these studies raise awareness for the need for treatment of diseases and disorders based on biochemical, rather than phenotypic presentation. This provides further impetus to proceed with efforts to identify the other disease genes underlying these disorders and to generate animal models as well as human cell model systems. For example, the continued development of iPSC technology might enable a deeper understanding of the molecular mechanisms underlying human disease, as well as improve our ability to achieve successful individualized therapies for treating patients. Ultimately, it will be the combination of understanding the pathogenesis of each disorder and the identification of small molecules that will enable us to treat patients.
Aside from enabling genetic testing for these RASopathy disorders, genotype/phenotype associations have been established for many, but much work is left to be done. These types of observations allow us to raise important biological and clinical questions. How are tissues/organs differentially affected by specific RASopathy mutations? If proteins are ubiquitously expressed, why are some organs/tissues spared while others are severely impacted? What is the basis of the specificity between altered gene, or even specific mutation, and the phenotype? How do we determine which pathways are affected by each of the mutations? Can inhibition of these ameliorate features of the disorders, and without side affects?
For treatment of NS-associated hypertrophy where the cause is associated with increased activation of MEK1/2 and/or ERK1/2, blockade of MAPK signaling seems efficacious. Indeed, in the Raf1L613V
model, treatment of the mice with the MEK inhibitor, PD0325901, blocked emergence of HCM as well as reversed it. However, clinical trials with PD325901 for the treatment of several types of cancers were terminated early due to ophthalmologic and neurologic toxicity (Haura et al. 2010
). Therefore, since RAS/MAPK signaling is present in a wide array of normal cells and RAS proteins control multiple cellular processes and target several downstream effectors, titrating down to the right level of inhibition to provide therapeutic efficacy without incurring intolerable side effects will be critical to maintain therapeutic advantage. Alternatively, more specifically targeted (and therefore more tolerable) drugs for this pathway are currently in the pipeline.
LS models, on the other hand, support the conclusion that excessive AKT/mTOR activity, not MAPK, is essential for the development and maintenance of HCM, and that a potential effective treatment for the reversal of HCM in these patients is rapamycin and/or its analogs. Rapamycin is commonly used as an immunosuppressive drug (Alexandre et al. 1999
). Nevertheless, it also has been used for other purposes, both in animal models and humans. Rapamycin has proven safe and beneficial in several therapeutic protocols; for instance, rapamycin is used for treatment of polycystic kidney disease in clinical trials (Serra et al. 2007
) and a rapamycin analog is now approved for the treatment of renal cancer (Dancey et al. 2009
Previous pharmacological studies have shown that treatment of cardiomyocytes with rapamycin could inhibit the hypertrophic response evoked by stimulation with various agonists (Boluyt et al. 1997
; Sadoshima and Izumo 1995
; Wang and Proud 2002
; Wang et al. 2000
). Rapamycin has also been shown to attenuate or reverse pressure overload- or constitutively active AKT-induced cardiac hypertrophy (Soesanto et al. 2009
) (Gao et al. 2006
; Shioi et al. 2003
), supporting a potential regulatory role for mTOR in HCM. However, recent evidence argues that mTOR expression either has no effect (Shen et al. 2008
) or may even be protective against stressed-induced pathological hypertrophy (Song et al. 2010
). Indeed, two independent studies indicate that complete ablation of mTOR (Zhang et al. 2010
) or the regulator of mTORC1, RAPTOR (Shende et al. 2011
), leads to DCM. These findings imply that rapamycin could have detrimental effects, and as a result, we cannot exclude the possibility that chronic inhibition and/or inhibition below physiological levels of mTOR could be deleterious in vivo
. Consequently, chronic and/or high-dosed inhibition of mTOR in patients with severe HCM and/or compromised contractile function may not be advisable. However, in the animal models of LS described herein, acute and/or low-dose administration of rapamycin was indeed able to rescue the hypertrophic phenotype without adverse effects on cardiac function (Marin et al. 2011
; Schramm et al. 2012
). Therefore, a potential short term and/or low-dose administration of rapamycin could have advantageous and beneficial effects in LS patients. Taken together, clinical trials of rapamycin and/or analogs should be considered for the treatment of LS-associated HCM.
We have made significant progress in understanding the differential signaling mechanisms affected by specific mutations in RASopathy disorders. We still have a long way to go. But given what we have learned so far, it is clear that the strategy for therapy must be based on the elucidation of the biological mechanism evoked by each specific mutation, rather than the physiological characteristics of the disorder itself.