mPRα mediates P4/Org OD02‐0 to improve the sensitivity of lung adenocarcinoma to EGFR‐TKIs via the EGFR‐SRC‐ERK1/2 pathway

Abstract

The discovery of epidermal growth factor receptor (EGFR) mutations has made EGFR tyrosine kinase inhibitors (EGFR‐TKIs) a milestone in the treatment for advanced non–small cell lung cancer (NSCLC). However, patients lacking EGFR mutations are not sensitive to EGFR‐TKI treatment and the emergence of secondary resistance poses new challenges for the targeted therapy of lung cancer. In this study, we identified that the expression of membrane progesterone receptor α (mPRα) was associated with EGFR mutations in lung adenocarcinoma patients and subsequently affected the efficacy of EGFR‐TKIs. Progesterone (P4) or its derivative Org OD02‐0 (Org), which is mediated by mPRα, increases the function of EGFR‐TKIs to suppress the proliferation, migration, and invasion of lung adenocarcinoma cells in vitro and in vivo. In addition, the mPRα pathway triggers delayed resistance to EGFR‐TKIs. Mechanistic investigations demonstrated that the mPRα pathway can crosstalk with the EGFR pathway by activating nongenomic effects to inhibit the EGFR‐SRC‐ERK1/2 pathway, thereby promoting antitumorigenic effects. In conclusion, our data describe an essential role for mPRα in improving sensitivity to EGFR‐TKIs, thus rationalizing its potential as a therapeutic target for lung adenocarcinomas.

FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer

“…In addition, high FGL1 expression may be related to the expression level of EGFR, which has been reported in L02 cells and several studies on liver injury [19,30,45,46]. FGL1 can inhibit L02 cell proliferation induced by activating the non-receptor tyrosine kinase SRC to induce EGFR phosphorylation [21]. It has also been observed that apoptosis of NSCLC cells is induced by inhibition of EGFR/STAT3 activation and promotion of PARP1 cleavage, regardless of the mutation status of EGFR [47].…”

“…Further, substantial evidence indicates that numerous cytokines related to cell proliferation play key roles in pathways that promote tumor cell proliferation and suppress their apoptosis [ 14 , 15 ], thereby significantly affecting patient prognosis. Benefited from the results above, some corresponding inhibitors like MEK inhibitors (trimetazidine) [ 16 , 17 ], MET-TKIs (tepotinib and cabozantinib) [ 18 , 19 ], PI3K inhibitor [ 20 ], and STAT3 and Src inhibitors [ 21 , 22 ] have been developed widely applied in clinical and showing good clinical effects. Some newly discovered cytokines, including YES (pp62c-yes) [ 23 ], YES/YES-associated protein 1 [ 24 ], and NF-1 [ 25 ], can increase the sensitivity of NSCLC cells to EGFR-TKIs by activating the AKT or MAPK pathway, showing great research benefits.…”

Microarray expression profiling of long noncoding RNAs in the progesterone‐treated lung cancer cells

“…The rate of P4 receptor expression in lung cancer tissues varies and it remains controversial as to whether it can predict the prognosis of lung cancer patients. Lu et al 22 demonstrated that mPRα expression was positively correlated with female gender, welldifferentiated status and a better prognosis in lung cancer patients. In addition, we previously showed that P4 reverses the EMT and inhibits lung cancer cell migration and invasion by binding to the mPRα.…”

“…In addition, we previously showed that P4 reverses the EMT and inhibits lung cancer cell migration and invasion by binding to the mPRα 23 . P4 treatment can also re‐sensitize lung cancer cells to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, and inhibit cell proliferation 22 . Nevertheless, the events mediating the protective effects of P4 in lung cancer are unclear.…”

FGL1 Regulates Acquired Resistance to Gefitinib by Inhibiting Apoptosis in Non-small Cell Lung Cancer

“…Further, substantial evidence indicates that numerous cytokines related to cell proliferation play key roles in pathways that promote tumor cell proliferation and suppress their apoptosis [14,15], thereby signi cantly affecting patient prognosis. Bene ted from the results above, some corresponding inhibitors like MEK inhibitors (trimetazidine) [16,17], MET-TKIs (tepotinib and cabozantinib) [18,19], PI3K inhibitor [20], and STAT3 and Src inhibitors [21,22] have been developed widely applied in clinical and showing good clinical effects. Some newly discovered cytokines, including YES (pp62c-yes) [23], YES/YES-associated protein 1 [24], and NF-1 [25], can increase the sensitivity of NSCLC cells to EGFR-TKIs by activating the AKT or MAPK pathway, showing great research bene ts.…”