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. 2020 Aug 18;10(23):10360–10377. doi: 10.7150/thno.49922

Figure 4.

Figure 4

LncRNAs-regulated resistance to targeted therapies beyond HER2. LncRNAs are emerging as pivotal regulators to mediate therapeutic tolerance to targeted therapies beyond HER2, including inhibitors of PI3K/AKT/mTOR pathway, CDKs and PARP. (A) LncRNAs-mediated resistance to therapies targeting PI3K/AKT/mTOR pathway. LINK-A directly binds to AKT and PIP3 to facilitate the enzymatic activation of AKT, leading to BC resistance to MK2206. AK023948 interacts with DHX9 and p85 to positively regulate AKT. In addition, IL-22-induced HOXB-AS5 expression could activate PI3K. Conversely, PTENP1 sponges miR-20a to release PTEN and negatively regulates PI3K/AKT/mTOR pathway. Furthermore, XIST can sequester HDAC3 to enhance the transcription of PHLPP1 and dephosphorylation of AKT. (B) LncRNAs-mediated resistance to therapies targeting CDKs. Lnc712 activates CDK2 through directly interacting with HSP90 and forming a complex of Lnc712/HSP90/Cdc37. In addition, MALAT1, TUG1, CCAT2 and LINC01089 are associated with the altered function of CDKs and Cyclins, which may be required for the drug resistance to CDK inhibitors in BC cells.