Yang, Yanan

e21631 Background: The efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without T790M mutation remains unclear in real-world practice. We investigated whether osimertinib can provide survival benefit in EGFR-mutant patients without T790M mutation after 1st/2nd generation TKI treatment. Methods: Between January 1, 2009, and March 31, 2019, 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as≥2nd-line EGFR-TKI treatment were identified at Mayo Clinic. The time to treatment failure of osimertinib was analyzed by the Kaplan-Meier (KM) estimates. The risk of death post diagnosis was analyzed by Cox proportional hazard models. Results: Among 417 EGFR-mutant patients, higher risk of death was found in patients with age above 65 years, non-adenocarcinoma, no surgery treatment, no radiation treatment, non-exon 19 deletion/exon 21 L858R mutation, higher ECOG PS (2-4), PD-L1 expression of 50% or more, bone metastasis, live metastasis, and adrenal metastasis (all p < 0.05). Moreover, osimertinib as ≥2nd-line TKI treatment in patients with or without T790M revealed lower risk of death compared to 1st/2nd generation TKI treatment without subsequent osimertinib (HR = 0.33; 0.46, and p = 0.0002; 0.0232, respectively). However, among patients receiving osimertinib as ≥2nd-line TKI treatment, patients with T790M did not have superior survival than those without (p = 0.2803). Among 154 patients receiving osimertinib, a higher risk of treatment failure for osimertinib was found in male (HR = 1.72; p = 0.0327), patients with 1st-line TKI duration ≤12 months (HR = 2.16; p = 0.0019), BMI drop > 10% (HR = 1.85; p = 0.0207), PD-L1 levels of 50% or more (HR = 4.28; p = 0.0008), and 1st-line TKI with afatinib (HR = 2.19; p = 0.0136). Nonetheless, osimertinib as ≥2nd-line TKI in patients without 790M mutation did not have higher risk of treatment failure than those with T790M (p = 0.1236). Conclusions: This is the first study to demonstrate that osimertinib can provide similar survival benefit in previously EGFR-TKI treated NSCLC patients without T790M mutation as those with T790M in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50% and may potentially gain benefit from optimizing treatment strategies including immunotherapy.

Abstract The acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a critical problem in lung cancer clinic, but the underlying mechanisms have remained incompletely understood. Although the TKI-induced or -selected genetic changes are known to drive resistance, resistance also occurs in tumor cells without genetic changes through poorly-characterized processes. Here, we show that the extracellular matrix (ECM) from various components of the tumor microenvironment, including neighboring tumor cells and fibroblasts, may be the driver of resistance in the absence of genetic changes. Unlike genetic changes, which may evolve during relatively long time of chronic EGFR TKI treatment to drive resistance, briefly culturing on de-cellularized ECM, or co-culturing with the ECM donor cells, immediately confers resistance to tumor cells that are otherwise sensitive to EGFR TKIs. We show evidence that collagen in the ECM may be its primary constituent driving resistance, at least partly through the collagen receptor Integrin-β1. Intriguingly, such effect of ECM and collagen is dose-dependent and reversible, suggesting a potential clinic-relevant application for targeting this effect. Collectively, our results reveal that the stromal ECM acts as a microenvironmental cue promoting EGFR TKI resistance in lung cancer cells, and targeting collagen and Integrin-β1 may be useful for treating resistance, especially the resistance without clearly-defined genetic changes, for which effective therapeutics are lacking. Citation Format: Ting Zhang, Lixia Guo, Yuanyuan Wang, Tao Ren, Yanan Yang. Stromal extracellular matrix is a microenvironmental cue promoting resistance to EGFR tyrosine kinase inhibitors in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 122.

Suppression of ZEB1 through miR-200 expression or HDAC inhibition with mocetinostat sensitizes resistant KRAS mutant lung cancers to MEK inhibition.

AbstractNOTCH1 is the prototype of the NOTCH family of single‐pass transmembrane receptors and regulates many basic processes during embryonic development and human pathogenesis. In core to NOTCH1 activation are proteolytic cleavages that release its intracellular domain (NICD1), which in turn translocates to the nucleus to regulate gene transcription. Macroautophagy (hereafter autophagy) has been shown to promote the degradation of NOTCH1, but the underlying mechanisms remain elusive. Here, we show that autophagy promotes the degradation of NOTCH1 by p62‐dependent binding between NICD1 and LC3, a component of the autophagosomes that execute autophagy. Strikingly, deleting any of the structural NICD1 domains fails to block the degradation of NICD1 by autophagy, and p62 binds to almost all these domains independently, indicating that p62 binds to multiple sites on NICD1 to promote its degradation. Intriguingly, inhibition of autophagy induces the accumulation of NICD1 in not only the cytoplasm but also the nucleus and increases the transcriptional activity of NICD1, and such regulation of nuclear NICD1 by autophagy is unique to NICD1 and not observed for all other NICDs (NICD2‐4). Collectively, our results suggest that autophagy tightly controls nuclear NOTCH1 activity through multiple p62 binding sites, and that modulating autophagy activity may be useful for treating NOTCH1 related human diseases. © 2018 IUBMB Life, 70(10):985–994, 2018

Lung cancer is one of the most common types of human malignancies and the leading cause of cancer-related death. Patients with surgically resectable early stage lung cancer are more likely curable, but currently only a small population of patients can be diagnosed at such a stage, partly due to our incomplete understanding of the biology of lung cancer and the lack of diagnostic and prognostic biomarkers. Recent studies have shown that NOTCH1 is a critical regulator of human carcinogenesis and has been implicated in multiple steps of cancer development and progression. Herein, we review recent findings about the role of NOTCH1 in lung cancer and discuss its potential usefulness as both a therapeutic target and a biomarker for lung cancer.

AbstractMicroRNA‐200 (miR‐200) has emerged as a regulator of the PI3K/AKT pathway and cancer cell growth. It was reported that miR‐200 can activate PI3K/AKT by targeting FOG2 (friend of GATA 2), which directly binds to the p85α regulatory subunit of PI3K. We found that miR‐200 was elevated in early stage lung adenocarcinomas when compared with normal lung tissues, and the expression of miR‐200 promoted the tumor spheroid growth of lung adenocarcinoma cells. We show that AKT activation was essential for such oncogenic action of miR‐200. However, depletion of FOG2 had little effect on AKT activation. By performing a reverse‐phase protein array, we found that miR‐200 not only activated AKT but also concomitantly inactivated S6K and increased IRS‐1, an S6K substrate that is increased on S6K inactivation. Depletion of IRS‐1 partially inhibited the miR‐200‐dependent AKT activation. Taken together, our results suggest that miR‐200 may activate AKT in lung adenocarcinoma cells through a FOG2‐independent mechanism involving IRS‐1. Our findings also provide evidence that increased miR‐200 expression may contribute to early lung tumorigenesis and that AKT inhibitors may be useful for the treatment of miR‐200‐dependent tumor cell growth. © 2015 IUBMB Life, 67(9):720–725, 2015