Sensitization of EGFR Wild-Type Non–Small Cell Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitor Erlotinib

Abstract

The benefit of EGFR-TKI in non-small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non-small cell lung cancer and the functional consequences and in animal models of patient-derived xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR-expressing cells to erlotinib, contrary to what happens in mutant EGFR cells and with a blocking EGFR antibody, both and The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers that enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, which should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy. .

Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations

“…Platinum-based chemotherapy and the first-generation TKIs have been used as the first-line treatment for NSCLC patients carrying wild-type and mutant EGFRs, respectively [15,16,23,24]. However, acquired drug resistance is inevitable after a progression-free period of approximately 9 to 13 months.…”

“…Cisplatin (CDDP), a platinum-based chemotherapeutic drug, has been commonly used to treat a wide range of solid malignancies, including lung cancer [10,11]. CDDP is the standard regimen in the first-line chemotherapy for patients with advanced stage NSCLC [10,12,13,14], especially patients carrying wild-type EGFR [15,16]. After cellular uptake, CDDP becomes a positively charged aquo complex that can interact with deoxyribonucleic acid (DNA) to form intra- and inter-strand cross-links, resulting in apoptosis induction [10,17].…”

The regulation of Neuropilin 1 expression by miR‐338‐3p promotes non‐small cell lung cancer via changes in EGFR signaling

“…However, some patients with lung cancer with wild-type EGFR benefit from EGFR-TKI therapy, 9,10 possibly because resistance to EGFR-TKIs can be mediated through multiple signalling pathways that converge upon cap-dependent translation in NSCLC cells expressing wild-type EGFR. 11,12 Interestingly, our previous study showed that CD73 affected the efficacy of EGFR-targeted therapies in NSCLC cells with wild-type EGFR. 13 Thus, based on the literature, we hypothesized that NRP1 plays a role in the EGF signalling pathway and that knockdown of NRP1 expression might sensitize NSCLC cells to therapeutic agents.…”

Influence of EGFR-activating mutations on sensitivity to tyrosine kinase inhibitors in a KRAS mutant non-small cell lung cancer cell line

“…In the present study, we aimed to assess the response to EGFR-TKIs of cancer cells with EGFR/KRAS co-mutations. Using CRISPR/Cas9 genome editing, we successfully generated isogenic cell lines with one or two copies of L858R EGFR mutation, one of the most common types of EGFR mutation [4], from A549 cells, a well-established cell line harboring homozygous G12S KRAS mutation but wild-type EGFR [20][21][22]. Comparison of TKI sensitivity among these cell lines showed that EGFR/KRAS co-mutated cells were more sensitive than parent cells, indicating that EGFR-TKIs may represent a treatment option for cancers harboring EGFR/KRAS co-mutation.…”