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  • Nonetheless questions remain For example why do


    Nonetheless, questions remain. For example, why do PTEN-mutated ADC L-Glutamine not always transform into SCC? Given that little is known about the discovery rate of co-developed activating EGFR mutations and PTEN deletions in the same tumor (Fig. A6 in Supplementary material), we used our observations to link our finding with activated EGFR pathway. EGFR promotes cellular proliferation through both the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway and the PI3K/AKT/mTOR pathway (Fig. 5a) [33]. With an activating EGFR mutation and intact PTEN function, cellular proliferation could rely mainly on the Ras/Raf/MAPK pathway (Fig. 5b). However, when EGFR TKI is applied to those patients, both the Ras/Raf/ERK and PI3K/AKT/mTOR pathways are suppressed, leading to cell death (Fig. 5c) [18]. Given the preclinical evidence and what our samples show, when EGFR pathway is suppression with TKI and PTEN or LKB1 are lost, cellular proliferation dependency on the PI3K/AKT/mTOR pathway might increase, which could lead to AST in tumors with an activating EGFR mutation (Fig. 5d). In this study, it was difficult to find substantial evidence linking AST with EGFR TKI failure. Perhaps, AST cases that follow the failure of EGFR TKI treatment without a known resistance mechanism support the possibility of AST as a novel mechanism of treatment failure [[6], [7], [8], [9],21]. However, some reports have proposed that activating the PI3K/AKT/mTOR pathway through PTEN loss without histologic changes could also contribute to EGFR TKI resistance [34]. Moreover, the presence of the EGFR p.T790 M mutation, which is a well-known resistance mechanism for first- and second-generation EGFR TKI [5], in the LC3 and LC4 patients weakens the relationship between TKI resistance and AST. Altogether, careful interpretation needs to be made in drawing out the connections between AST and EGFR TKI resistance. Although we proposed an additional dataset and hypothesis for AST based on somatic mutations and copy number alterations, our ability to validate the pathway activity is limited by the unavailability of gene expression data. At the same time, we have no clear explanation for the contribution of the single copy-number loss of PTEN or LKB1 or the mutation of RICTOR or PIK3CA to AST. Nonetheless, our paired sample analysis has unique value because all the post-samples possess an initially identified EGFR mutation, which means that the AST is caused by a lineage transition of the existing clone rather than the development of a new primary tumor. In conclusion, using paired human AST samples, we present positive evidence for the correlation between the PI3K/AKT/mTOR pathway and an ADC to SCC lineage transition that could potentially broaden understanding of the spectrum of mechanisms that lead to EGFR TKI resistance in EGFR-mutated lung ADC.
    Conflict of interest
    Funding source This paper was supported by the following grant(s): The National R & D Program for Cancer Control, Ministry of Health & Welfare, Korea (1720180)
    Introduction Epidermal Growth Factor Receptor (EGFR) mutations occur in approximately 30% of cases of non-small cell lung cancer (NSCLC) and are important drivers in the development of lung adenocarcinoma [1]. The last few years have seen the development of several FDA approved EGFR targeted therapies, which have significantly improved progression free survival while achieving more favorable side effect profiles compared to chemotherapy for patients with sensitizing mutations in EGFR [[2], [3], [4]]. However, despite the development of new therapies, acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is inevitable and progression usually occurs within 10–20 months of starting treatment [5]. Although development of EGFR TKI resistance is virtually universal, the mechanisms of resistance are incompletely understood. First generation TKIs (erlotinib, gefitinib) were the standard of care for many years and continue to be widely used despite development of second and third generation drugs. For patients on first generation TKIs, observed mechanisms of resistance include development of T790 M resistance mutations in the EGFR domain in up to two-thirds, up-regulation of proteins in “bypass” pathways such as HER3, MET, IGF-1R, or mutations in HER2 or PIK3CA [1].