Figure 3.

Adaptive upregulation of compensatory signalling limits the efficacy of EGFR-MAPK pathway inhibition. A: SHP2 is a convergent signalling node downstream of multiple RTKs. Inhibition of MEK induces SHP2 activation through increased RTK signalling and possibly other direct mechanisms, leading to ERK activity rebound. Inhibition of SHP2 prevents MEKi-induced ERK rebound through limiting the activity of RAS; B: upregulation of HER3 mediates adaptive resistance to EGFR in TNBC cells. PYK2 normally binds to the E3 ligase NEDD4 to inhibit it from degrading HER3. Inhibition of PYK2 destabilizes HER3 and resensitizes TBNC cells to EGFR inhibitors