Role of mTOR inhibition in preventing resistance and restoring sensitivity to hormone-targeted and HER2-targeted therapies in breast cancer

Abstract

Even with hormone-targeted and human epidermal growth factor receptor 2 (HER2)-targeted anticancer agents, intrinsic resistance or acquired resistance are common occurrences in estrogen receptor-positive and HER2-positive breast cancers, respectively. Potential mechanisms for resistance to targeted agents include steric inhibition imposed by other cellular elements, molecular changes in the target receptor, alterations in the regulation of downstream signaling components, compensatory cross-talk with other signaling pathways, and pharmacogenetic alterations in the host. Evidence suggests that both hormone receptor-positive tumors and HER2-overexpressing tumors use the phosphoinositide 3-kinase/Akt/ mammalian target of rapamycin (mTOR) pathway to escape control of antihormone and anti-HER2 therapies. The combination of mTOR inhibitors with hormone-targeted or HER2-targeted therapies appears to be a promising strategy for overcoming resistant disease and preventing the development of resistance.

Figure 1. The PI3K/Akt/mTOR signaling pathway.

4EBP1=4E–binding protein 1; AMPK=adenosine monophosphate-activated protein kinase; ASK1=apoptosis signal-regulating kinase 1; ATP=adenosine-5’-triphosphate; BAD=BCL2-associated agonist of cell death; eEF2K= eukaryotic elongation factor-2 kinase; eIF4B=eukaryotic initiation factor 4B; eIF4E=eukaryotic initiation factor 4E; FKBP12=FK506-binding protein, 12 kD; FOXO=forkhead box O1; GDP=guanosine diphosphate; GSK3=glycogen synthase kinase 3; GTP=guanosine-5’-triphosphate; IRS1=insulin receptor substrate 1; mLST8=mTOR-associated protein, LST8 homolog; mTOR=mammalian target of rapamycin; mTORC1=mTOR complex 1; mTORC2=mTOR complex 2; PDCD4=programmed cell death 4; PDK1=phosphoinositide-dependent kinase 1; PI3K=phosphatidylinositol 3-kinase; PIP2=phosphatidylinositol (4,5) biphosphate; PIP3=phosphatidylinositol (3,4,5) triphosphate; PRAS40=proline-rich Akt substrate 40; PTEN=phosphatase and tensin homolog; Rheb=Ras homolog enriched in brain; S6=ribosomal protein S6; S6K=ribosomal protein S6 kinase; SIN1=stress-activated mitogen-activated protein kinase associated protein 1; TSC1=tuberous sclerosis complex 1; TSC2=tuberous sclerosis complex 2. Reprinted from McAuliffe PF et al. Deciphering the role of PI3K/Akt/ mTOR pathway in breast cancer biology and pathogenesis.

Figure 2. TOR plays a central role in cell growth regulation by integrating signals from growth factors, nutrients, and cellular energy levels

4E–BPs=4E–binding proteins; EIF4E=eukaryotic initiation factor 4E; FOXO=forkhead box O1; GRB2=growth factor receptor-bound protein 2; GTP=guanosine-5’-tri-phosphate; mTOR=mammalian target of rapamycin; mTORC1=mTOR complex 1; PDK1=phosphoinositide-dependent kinase 1; PI3K=phosphatidylinositol 3-kinase; PIP=phosphatidylinositol triphosphate; PTEN=phosphatase and tensin homolog; RAPTOR=regulatory-associated protein of mTOR; Rheb=Ras homolog enriched in brain; TOR=target of rapamycin; TSC1=tuberous sclerosis complex 1; TSC2=tuberous sclerosis complex 2. Reprinted from McAuliffe PF et al. Deciphering the role of PI3K/Akt/mTOR pathway in breast cancer biology and pathogenesis.