Table 4 Illustration of experimental and clinical outcomes in ER+ and HER2+ breast cancer reproduced by the model

Drug inhibition of MEK in HER2+ breast cancer cells leads to increased HER2/HER3 heterodimer formation and higher PI3K activation

(Turke et al., 2012)

High HER3 expression induces resistance to PI3K inhibitors, which is overcome by HER3 blockade, in HER2-amplified and/or PIK3CA-mutant breast cancer cell lines and brain metastases of mouse xenografts.

((Kodack et al., 2017); (Chakrabarty et al., 2012))

High PIM expression is a resistance mechanism to PI3K inhibitors in ER+ (PIM1/2/3) and HER2+ (PIM2) breast cancer cell lines. High PIM1/3 expression is observed in biopsies of ER+ human tumors treated with PI3K inhibitors.

((Le et al., 2016); (Zwang et al., 2017))

High PDK1/SGK1 expression is a resistance mechanism to PI3K inhibitors in HER2+ breast cancer cell lines and mouse xenografts tumors. High SGK1 expression and activity in breast cancer tumor samples causes intrinsic resistance to PI3K inhibitors.

(Castel et al., 2016)

High PDK1 and AKT2 expression are putative resistance mechanisms to PI3K inhibitors; they are observed in biopsies of ER+ human tumors treated with PI3K inhibitors.

(Le et al., 2016)

Inhibition of PI3K induces a rapid downregulation of MAPK signaling and induction of apoptosis in ER+ and HER2+ breast cancer cell lines and mouse xenograft tumors. In HER2+ breast cancer cell lines, MAPK activity is reactivated following the induction of RTKs.

((Costa et al., 2015); (Will et al., 2014); (Ebi et al., 2013))

Inhibition of AKT (directly by AKT inhibitors or indirectly by mTOR or PI3K inhibitors) induces the activity of the transcription factor FOXO3, which upregulates a shared set of RTKs, including HER3, IGF1R, in HER2+ breast cancer cell lines and mouse xenografts tumors.

((Chandarlapaty et al., 2011); (Rodrik-Outmezguine et al., 2011); (Chakrabarty et al., 2012))

Inhibition of PI3K in ER+ breast cancer cell lines induces the transcription factor activity of FOXO3, which binds the promoters of ESR1 and HER3, and upregulates their expression. The upregulation of ESR1 expression in response to PI3K inhibitors has also been observed in ER+ mouse xenograft tumors and ER+ human breast cancer tumor biopsies.

((Bosch et al., 2015); (Kodack et al., 2017))