Table 2.
Targeting Signaling Pathways Involved in Cancer Biology for Controlling/Regressing Enhanced Proliferation, Survival, and Apoptosis Resistance of Lung Vascular Cells in Pulmonary Hypertension
| Molecule/Pathway | Cell Type | Status in PAH/Experimental PH | Function | Inhibitor(s)/Activator(s) Tested | Effect of Inhibitor(s)/Activator(s) |
|---|---|---|---|---|---|
| RTKs | |||||
| PDGFR | PASMCs | PASMCs: | PASMCs: | Imatinib | Inhibits proliferation of human IPAH and rat MCT-PH PASMCs (219) |
| PAECs | ↑ Human IPAH | ↑ Proliferation | Reverses MCT-PH in rats (61, 219) | ||
| ↑ Rat HPH | ↓ Apoptosis | Showed efficacy in phase II (59) and III (196) trials | |||
| Improves PVR and 6MWD in patients with severe PAH (196) | |||||
| Nilotinib | Reverses pulmonary vascular remodeling in rat MCT-PH and HPH (61) | ||||
| EGFR | PASMCs | No significant alterations in experimental/clinical PH | PASMCs: ↑ Proliferation |
PKI166 | Mediates apoptosis in PA organ culture (98) Attenuates rat MCT-PH (98) |
| ↓ Apoptosis | Gefitinib | Attenuates rat MCT-PH (127) No significant benefits in mouse HPH (127) |
|||
| Erlotinib | Attenuates rat MCT-PH (127) No significant benefits in mouse HPH (127) |
||||
| Lapatinib | No therapeutic benefit in experimental PH (127) | ||||
| FGFR | PAECs PASMCs |
↑ Human IPAH (FGF-2) ↑ Rat MCT-PH (FGF-2, FGFR1) |
PAECs: ↑ Proliferation PAECs: ↑ Proliferation |
SU5402 | Reverses rat MCT-PH (128) |
| Ras/Raf/MAPK | PAECs | ↑ Rat MCT-PH (p-Raf-1, p-ERK) ↑ Rat HPH ↑ Rat SuHx-PH (p-ERK, p-MEK1/2) |
PAECs: ↑ Proliferation Cardiomyocytes: ↓ Vasopressin-induced hypertrophy |
Sorafenib | Attenuates rat MCT-PH (81) Improves RV function in PAB rats (95) Attenuates rat HPH and SuHx-PH (56) |
| PI3K | PASMCs PAECs |
Unknown | PASMCs: ↑ Mitogen-induced proliferation and migration PAECs: ↑ Proliferation ↓ Apoptosis ↑ NO production and vasodilation |
LY294002 | Inhibits growth factor-induced PASMC proliferation and migration (159) Attenuates development of HPH in rats (17) |
| Akt | PASMCs PAAFs PAECs | PASMCs: ↑ Human IPAH ↑ Rat HPH PAAFs: ↑ Human IPAH ↑ Rat HPH PAECs: Unknown |
PASMCs: ↑ Proliferation ↓ Apoptosis PAAFs: ↑ Proliferation PAECs: ↑ Proliferation ↓ Apoptosis ↑ NO production and vasodilation |
Triciribine | Attenuates development of HPH in rats (17) |
| mTORC1 | PASMCs | ↑ Human IPAH ↑ Rat HPH ↑ Rat MCT-PH |
↑ Proliferation | Rapamycin Everolimus |
Inhibits proliferation of human IPAH PASMCs (97) Inhibits proliferation of rat MCT-PH PASMCs (226) Improves PVR and 6MWD in patients with severe PAH (23) |
| mTORC2 | PASMCs | ↑ Human IPAH ↑ Rat HPH ↑ Rat MCT-PH |
↑ Proliferation ↓ Apoptosis |
PP242 (dual) | Inhibits proliferation, induces apoptosis in human IPAH PASMCs (97) Reverses pulmonary vascular remodeling in rat HPH (97) |
| Notch3/HES | PASMCs | ↑ Human PAH ↑ Mouse HPH |
↓ Differentiation ↑ Proliferation |
DAPT | Inhibits human IPAH growth (118) Reverses mouse HPH (118) |
| FoxOs | PASMCs | ↓ Human PAH ↓ Rat MCT-PH ↓ Rat SuHx-PH |
↑ Proliferation ↓ Apoptosis |
Paclitaxel Abraxane |
Inhibits human IPAH growth (31) Reverses rat MCT-PH (31) Reverses rat SuHx-PH (31, 190) |
Definition of abbreviations: 6MWD, 6-min-walk distance; Akt, v-akt murine thymoma viral oncogene homolog; DAPT, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGF-2, fibroblast growth factor 2; FGFR, fibroblast growth factor receptor; FoxO, forkhead-box class O; HES, hairy/enhancer of split; HPH, hypoxia-induced pulmonary hypertension; IPAH, idiopathic pulmonary arterial hypertension; MAPK, mitogen-activated protein kinase; MCT-PH, monocrotaline-induced PH; MEK, MAPK/ERK kinase; mTOR, mechanistic target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PA, pulmonary artery; PAB, pulmonary artery banding; PAAFs, pulmonary artery adventitial fibroblasts; PAECs, pulmonary artery endothelial cells; PAH, pulmonary arterial hypertension; PASMCs, pulmonary artery smooth muscle cells; PDGFR, platelet-derived growth factor receptor; PH, pulmonary hypertension; PI3K, phosphatidylinositol 3-kinase; PVR, pulmonary vascular resistance; RTK, receptor tyrosine kinase; RV, right ventricular; SuHx, Sugen/hypoxia.
Reused, with permission, from Pullamsetti SS, et al., 2017 (140)/with permission of American Thoracic Society.