scholarly journals Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors

2018 ◽  
Author(s):  
Deborah Ayeni ◽  
Braden Miller ◽  
Alexandra Kuhlman ◽  
Ping-Chih Ho ◽  
Camila Robles-Oteiza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Immune Cells ◽  
Kinase Inhibitors ◽  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Lung Tumors ◽  
Combination Strategies ◽  
Before And After ◽  
Egfr Mutant

AbstractEpidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Using mouse models, we studied the immunological profile of mutantEGFR-driven lung tumors before and after erlotinib treatment. We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. Erlotinib treatment also led to increased maturation of myeloid cells and an increase in CD40+ dendritic cells. Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlights potential avenues for investigation of targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.

scholarly journals Tumor immune microenvironment in non-small cell lung cancer with EGFR mutation before and after EGFR-TKIs treatment

2021 ◽  
Author(s):  
chao wang ◽  
lihui liu ◽  
sini li ◽  
hua bai ◽  
jie wang
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Treatment Time ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Before And After ◽  
Almost All ◽  
Egfr Tkis

Lung cancer is the most common cancer and a leading cause of death from cancer in men and women in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are considered as the first-line treatment of EGFR mutated NSCLC. However, almost all patients eventually develop acquired resistance to EGFR-TKIs, with a median PFS of 9-14 months. With the development of immunotherapy, people realize that the interaction between tumor immune microenvironment (TIME) and tumor cells can also affect EGFR-TKIs treatment. TIME contains a variety of elements and previous researches of TIME in EGFR-TKIs therapy on NSCLC are decentralized. Here, we review the characteristics of TIME in NSCLC from EGFR-TKIs therapy and its role in TKIs resistance.

Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas

2017 ◽  
Vol 35 (26) ◽  
pp. 3065-3074 ◽  
Author(s):  
June-Koo Lee ◽  
Junehawk Lee ◽  
Sehui Kim ◽  
Soyeon Kim ◽  
Jeonghwan Youk ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Cell Transformation ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Complete Inactivation ◽  
Genetic Predictors ◽  
Egfr Mutant ◽  
Egfr Tki

Purpose Histologic transformation of EGFR mutant lung adenocarcinoma (LADC) into small-cell lung cancer (SCLC) has been described as one of the major resistant mechanisms for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the molecular pathogenesis is still unclear. Methods We investigated 21 patients with advanced EGFR-mutant LADCs that were transformed into EGFR TKI–resistant SCLCs. Among them, whole genome sequencing was applied for nine tumors acquired at various time points from four patients to reconstruct their clonal evolutionary history and to detect genetic predictors for small-cell transformation. The findings were validated by immunohistochemistry in 210 lung cancer tissues. Results We identified that EGFR TKI–resistant LADCs and SCLCs share a common clonal origin and undergo branched evolutionary trajectories. The clonal divergence of SCLC ancestors from the LADC cells occurred before the first EGFR TKI treatments, and the complete inactivation of both RB1 and TP53 were observed from the early LADC stages in sequenced tumors. We extended the findings by immunohistochemistry in the early-stage LADC tissues of 75 patients treated with EGFR TKIs; inactivation of both Rb and p53 was strikingly more frequent in the small-cell–transformed group than in the nontransformed group (82% v 3%; odds ratio, 131; 95% CI, 19.9 to 859). Among patients registered in a predefined cohort (n = 65), an EGFR mutant LADC that harbored completely inactivated Rb and p53 had a 43× greater risk of small-cell transformation (relative risk, 42.8; 95% CI, 5.88 to 311). Branch-specific mutational signature analysis revealed that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)–induced hypermutation was frequent in the branches toward small-cell transformation. Conclusion EGFR TKI–resistant SCLCs are branched out early from the LADC clones that harbor completely inactivated RB1 and TP53. The evaluation of RB1 and TP53 status in EGFR TKI–treated LADCs is informative in predicting small-cell transformation.

scholarly journals Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

2015 ◽  
Vol 112 (22) ◽  
pp. 6955-6960 ◽  
Author(s):  
Hsin-Yung Yen ◽  
Ying-Chih Liu ◽  
Nai-Yu Chen ◽  
Chia-Feng Tsai ◽  
Yi-Ting Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Cancer Progression ◽  
Conformational Changes ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Kinase Activation ◽  
Downstream Signaling ◽  
Egfr Mutant

Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKI-sensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKI-resistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKI-resistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.

scholarly journals Nonsmall Cell Lung Cancer Therapy: Insight into Multitargeted Small-Molecule Growth Factor Receptor Inhibitors

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Mridul Roy ◽  
Yu-Hao Luo ◽  
Mao Ye ◽  
Jing Liu
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Cancer Therapeutics ◽  
Nonsmall Cell Lung Cancer ◽  
Combination Strategies ◽  
Self Sufficiency

To date, lung cancer is the leading cause of cancer-related death worldwide, among which nonsmall cell lung cancer (NSCLC) comprises about 85%. Taking into account the side effects of surgery, radiation, platinum-based doublet chemotherapy, and the growth self-sufficiency characteristic of cancer cells, drugs have been discovered toward growth factor receptor (GFR) to treat NSCLC. As expected, these drugs provide a greater benefit. To increase the efficacy of such growth factor receptor tyrosine kinase inhibitors (RTKIs), coinhibition of GFR signaling pathways and combination of inhibitors along with radiation or chemotherapy have drew intense insight. Although clinical trials about single-agent RTKIs or their combination strategies suggest their increase potency against cancer, they are not beyond adverse effects, and sometimes the effects are more deadly than chemotherapy. Nevertheless the hope for RTKIs may be proved true by further researches and digging deep into cancer therapeutics.

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