PI3K inhibition sensitizes EGFR wild‑type NSCLC cell lines to erlotinib chemotherapy

Abstract

Tyrosine kinase inhibitors (TKIs) bring significant benefits for patients with cancers harboring epidermal growth factor receptor (EGFR) mutations. However, after treatment for a certain period, most patients ultimately acquire resistance. Numerous studies indicated that PI3K has an important role in tumor cell growth and drug sensitivity. Furthermore, inhibition of PI3K may lead to sensitization of non-small cell lung cancer (NSCLC) cells to EGFR-TKIs. The aim of the present study was to explore whether LY294002, an inhibitor of PI3K, is able to improve the sensitivity of NSCLC cell lines with wild-type EGFR to the EGFR-TKI erlotinib. An MTT assay was used to examine the effect of combined treatment with LY294002 and erlotinib on cell survival of two EGFR wild-type NSCLC cell lines, NCI-H661 and NCI-H460. Furthermore, flow cytometry was used to assess apoptosis in NCI-H661 and NCI-H460 cells after treatment with erlotinib and LY294002. In addition, the expression of downstream proteins was detected by western blot analysis. The results indicated that the number of viable NCI-H661 and NCI-H460 cells was dose-dependently reduced by erlotinib or LY294002. Compared to treatment with erlotinib alone, the cell apoptosis was enhanced if combined treatment of erlotinib and LY294002 was performed in NCI-H661 cells. Furthermore, combination treatment of erlotinib and LY294002 resulted in a significant reduction of phosphorylated p70S6K levels in NCI-H661 [PI3K catalytic subunit alpha (PI3KCA) wild-type] cells. However, this phenomenon was not observed in the NCI-H460 cell line (PIK3CA mutant-type). In conclusion, the present study indicated that inhibition of PI3K may have the potential to improve the sensitivity of NSCLC cells to an EGFR-TKI. However, the therapeutic effect may depend on the mutation status of PIK3CA.

Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy

“…[ 22 ] PI3K‐AKT‐mTOR inhibition was also reported to sensitize lung cancer cells to or overcome resistance to EGFR‐TKIs. [ 30 , 31 , 32 , 33 , 34 , 35 ] BET inhibition was reported to delay the acquired resistance to anti‐EGFR antibody in head and neck squamous cell carcinoma, and synergize with anti‐HER2 TKIs in lung cancer and breast cancer. [ 36 , 37 , 38 ] The results showed that JQ1 and copanlisib combined with osimertinib led to significantly more potent inhibitory effect than using these drugs alone in BASC‐A tumoroids (Figure S4E , Supporting Information).…”

LPCAT1 promotes gefitinib resistance via upregulation of the EGFR/PI3K/AKT signaling pathway in lung adenocarcinoma

“…Further in vivo experiments demonstrated that LY294002 substantially circumvented resistance to gefitinib and promoted gefitinib-induced shrinkage of xenograft tumors on the basis of LPCAT1 knockdown. Of coincidence, the study by Zhou et al reported that LY294002 exerted the activity of sensitizing EGFR wild-type NSCLC cell lines to erlotinib chemotherapy [29]. These results strongly indicate that LPCAT1 can contribute to gefitinib resistance in LUAD by activating the EGFR/PI3K/AKT signaling pathway.…”

NSAIDs Overcome PIK3CA Mutation-Mediated Resistance to EGFR Inhibition in Head and Neck Cancer Preclinical Models

“…Moreover, in HPV-positive patients, those with PIK3CA mutations were recently found to have an increased chance of recurrence, and worse disease-free survival rates [25]. Preclinical studies have indicated that the dual inhibition of the PIK3CA and EGFR pathways demonstrates synergistic cell killing in head, neck [26] and lung cancer models [27].…”