Figure 8. Modeling of palbociclib resistance in KRAS-mutant NSCLC cells and effects of MAP kinase pathway inhibition.

A. KRAS-mutant NSCLCs signal via the MAP kinase pathway to stimulate cell cycle progression. B. A bFGF autocrine/paracrine loop propagates and maintains palbociclib resistance in NSCLC. Increased signals through MEK-ERK1/2-mTOR enhance the expression, assembly and activity of cyclin D-CDK6, which promotes palbociclib-resistant proliferation and growth and enhances the transcription of the FGFR ligand bFGF. bFGF is secreted, where its activates its receptor to further enhance MEK-ERK1/2 signaling within the individual resistant cell as well as in neighboring cells. Increased MAP kinase activity in the palbociclib-resistant state also leads to increased cyclin E-CDK2 activity. C. MAP kinase pathway inhibition is expected to disrupt the autocrine loop, reducing the expression of D-cyclins and CDK6. MEK inhibition causes increased expression of p27^Kip1, as well as a redistribution of p27^Kip1 from CDK4/6 to CDK7 with maintenance of the association of p27^Kip1 with CDK2. These events block the activating phosphorylation of CDK2 mediated by CAK, and directly block CDK2 activity. Therefore, MAP kinase inhibition reduces the activity of all G1 CDK complexes in palbociclib-resistant cells.