We have reported previously that simultaneous inhibition of PI3Kα and CDK4/6 synergistically suppressed KRAS-mutated non-small cell lung cancer.47 Concurrent targeting PI3K and cell cycle progression has displayed synergism in a variety of tumors, including breast cancer48,49 and lung squamous cell carcinoma,50 and attenuated ABCB1/P-gp mediated multi-drug resistance.51 We demonstrated that palbociclib extended the efficacy of CYH33 via suppressing phosphorylation of Rb and thus reinforcing the p21-Rb-E2F1-SKP2 loop. Here, SKP2 is linked to squamous cell lung carcinoma.