A case report of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR -tyrosine kinase inhibitors with T790M mutation and epithelial-to-mesenchymal transition

Abstract

Although a secondary mutation and the epithelial-to-mesenchymal transition (EMT) are encountered very often in patients received the EGFR-TKI targeted treatment. The entire detrimental morphological change of the cancer entity was rare reported. Herein we report a case that acquired resistance to EGFR-TKI with T790M mutation and complete EMT morphological change of the tumor tissue. The primary lung tumor from a 52-year-old woman was diagnosed with moderate differentiated adenocarcinoma, with intensively positiveTTF-1 and E-cadherin in differentiated glandular structure but not the budding cancer cell cluster which with an intensive Vimentin staining. Molecular analysis revealed an EGFR exon 19 deletion and with an excellent response to Gefitinib treatment. Microscopic examination of recurred tumor specimens revealed a diffuse poorer differentiated proliferation of atypical cells. Immunostaining showed intensive Vimentin but almost completely negative for E-cadherin and TTF-1. Genetic analyses revealed T790M mutation. It is worth noting that rare clinical studies have been reported that acquired EGFR-TKI resistant lung adenocarcinoma underwent T790M mutation and almost complete EMT together. More significantly, the similarity of poorly differentiated cancer cell cluster in the primary lesions to recurred tumor lesions, which may pre-harbor drug resistance mutation should not be neglected underneath the predominant morphologic patterns.

Clinical Impact of the Epithelial-Mesenchymal Transition in Lung Cancer as a Biomarker Assisting in Therapeutic Decisions

“…Only few clinical reports evaluated EMT in patients with tumors harboring activating EGFR mutations. Those observations associated mesenchymal features with EGFR-TKI resistance [Miyoshi et al, 2015;N. Zhang et al, 2017;Poh et al, 2018].…”

The FGFR1 V561M Gatekeeper Mutation Drives AZD4547 Resistance through STAT3 Activation and EMT

“…This demonstrates a major pitfall of utilizing single targeted therapies in the clinic; the mechanism of drug resistance has a secondary effect of increasing the metastatic potential of the tumor. EMT has also been identified as a mechanism of drug resistance in EGFR T790M-driven cancers (28,29,55), suggesting that this may be a common phenomenon among RTK gatekeeper mutations.…”

“…The gatekeeper mutants of EGFR, PDGFR, c-ABL, and Src were shown to have activated kinase activity and an increased rate of cellular transformation (16). In addition, the EGFR T790M gatekeeper mutation has been shown to promote EMT (28)(29)(30). Previous studies in our lab have kinetically characterized V561M FGFR1 and demonstrated an increase in the k cat of V561M FGFR1 relative to wild type (WT).…”

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

“…Furthermore, analysis of a primary tumor sample from a patient with EGFR-TKI-resistant lung ADC showed a complete EMT phenotype with the T790M mutation. 132 The role of IGF1R signaling in the development of EGFR-TKI resistance is well known 133 ; thus, Li et al further explored the mechanism of IGF1R signalling-mediated EGFR-TKI resistance in lung cancer. It was revealed that IGF1R/Akt/Erk/NF-κB signaling is activated during EMT-mediated EGFR-TKI resistance in EGFR-mutated NSCLC.…”

“…These results strongly support that EMT phenotype plays an important role in sensitivity and resistance of EGFR‐TKIs in lung cancer. Furthermore, analysis of a primary tumor sample from a patient with EGFR‐TKI‐resistant lung ADC showed a complete EMT phenotype with the T790M mutation 132 . The role of IGF1R signaling in the development of EGFR‐TKI resistance is well known 133 ; thus, Li et al further explored the mechanism of IGF1R signalling‐mediated EGFR‐TKI resistance in lung cancer.…”