In this study, we report for the first time that, through the specific inhibition of PI3K 110α and 110β subunits of PI3K with BAY-1082439 and via Crispr/Cas9 gene knockout method, two ABC transporters, P-gp/ABCB1 and BCRP/ABCG2 that contribute to the MDR of cancers were downregulated and the drug resistance was reversed in human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. This evidence concerns the gene PIK3CD and squamous cell carcinoma.