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Figure 4. Resistance mechanisms to RAS/PI3K pathway targeting in RMS. (A) Monotherapies targeting RAS or PI3K pathway components often induce compensatory feedback mechanisms, resulting in reactivation of RAS/PI3K signaling or upstream RTKs. For example, MEK inhibition by trametinib leads to upregulation of IGF1R, which in turn reactivates the PI3K pathway; (B) Inhibition of a specific RTK can also lead to compensatory signaling through alternative RTKs. For instance, PDGFR inhibition by imatinib may be bypassed through alternative activation of the RAS/PI3K axis via EPHB4. RAS: Rat sarcoma; PI3K: phosphoinositide 3-kinase; RMS: rhabdomyosarcomas; RTKs: receptor tyrosine kinases; MEK: mitogen-activated protein kinase kinase; IGF1R: insulin-like growth factor-1 receptor; PDGFR: platelet-derived growth factor receptor; EPHB4: ephrin type-B receptor 4; RAF: rapidly accelerated fibrosarcoma; ERK: extracellular signal-regulated kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin.