Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer

Drug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR- and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.

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Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer

10.1101/2020.04.28.066241 ◽

2020 ◽

Author(s):

Patricia L. Theard ◽

Erin Sheffels ◽

Nancy E. Sealover ◽

Amanda J. Linke ◽

David J. Pratico ◽

...

Keyword(s):

Egfr Signaling ◽

Rtk Signaling ◽

Adherent Culture ◽

Effector Pathways ◽

Tki Treatment ◽

Cancer Spheroids ◽

Proximal Signaling ◽

Egfr Mutated ◽

Egfr Tki

AbstractDrug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR- and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.

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The Efficacy of Traditional Chinese Herbal Medicine in the Treatment of EGFR Mutated Stage IV Pulmonary Adenocarcinoma Patients Who Received First-Line EGFR-TKI Treatment

Integrative Cancer Therapies ◽

10.1177/1534735416645181 ◽

2016 ◽

Vol 16 (1) ◽

pp. 126-131 ◽

Cited By ~ 5

Author(s):

Hsiu-Ying Hung ◽

Yen-Han Tseng ◽

Chia-Miao Liao ◽

Sung-Yi Chen ◽

Ta-Peng Wu ◽

...

Keyword(s):

Overall Survival ◽

Herbal Medicine ◽

Chinese Herbal Medicine ◽

Stage Iv ◽

Pulmonary Adenocarcinoma ◽

First Line ◽

Chinese Herbal ◽

Tki Treatment ◽

Egfr Mutated ◽

Egfr Tki

Background. Chinese herbal medicine (CHM) has been used for thousands of year in Eastern countries. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment is the standard treatment in stage IV pulmonary adenocarcinoma patients who had tumor EGFR mutations. This study was to find the efficacy of CHM on lung cancer treatment. Materials and Methods. We retrospectively reviewed chart records of our stage IV EGFR-mutated pulmonary adenocarcinoma patients who received first-line EGFR-TKI treatment from January 2010 to September 2014. Results. Total, 527 patients were studied. Among them, 34 patients received CHM treatment, including 24 patients who received CHM treatment from the beginning of first-line EGFR-TKI treatment and 10 patients who started to receive CHM treatment after their disease had progressed to EGFR-TKI treatment. Median progression-free survival (PFS) of first-line EGFR-TKI treatment was numerically better in patients who also received CHM than those who did not (12.1 months vs 10.5 months, P = .7668). Overall survival of those 24 patient who received CHM treatment together with EGFR-TKI was 30.63 months (95% CI = 11.7 to not reached), compared to 23.67 months in the remaining patients (95% CI = 21.37-26; hazard ratio = 0.75; P = .399). No increase of CHM-related toxicities was found during CHM treatment, compared with EGFR-TKI treatment alone ( P > .05). Conclusion. Alternative CHM treatment during first-line EGFR-TKI treatment did no harm to the patients and PFS and overall survival was numerically better, although not significant, than those patients who did not receive CHM treatment.

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Optimisation of EGFR TKI efficiency in the therapeutic scheme of EGFR wild-type lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e18532 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e18532-e18532

Author(s):

Mathilde Cabart ◽

Judith Raimbourg ◽

Lisenn Lalier ◽

Jaafar Bennouna ◽

Francois Vallette

Keyword(s):

Lung Cancer ◽

Tyrosine Kinases ◽

Receptor Tyrosine Kinases ◽

Wild Type ◽

Short Term ◽

Egfr Ligands ◽

Egfr Mutated ◽

Egfr Tki

e18532 Background: EGFR tyrosine kinase inhibitors (EGFR TKI) have improved the therapeutic care of lung cancer patients but only a small sub-population of patients, namely those harboring EGFR-mutated tumors, benefit from this therapy. The observation that EGFR TKI enhance prognosis and quality of life in all patients when used as second line or maintenance treatment impelled us into the search of potential markers of the optimal introduction kinetics of EGFR TKI in the therapeutic scheme. Methods: We used lung cancer cell lines harboring either wild-type or mutated EGFR (NCI-H1650, NCI-H1975) to study the consequences of cisplatin treatment in vitro on the consecutive sensitivity to erlotinib. Results: Sub-lethal cisplatin pretreatment (3µM) enhances erlotinib toxicity in EGFR wild-type, but not EGFR mutated cells (A549 IC50 drops from 28 to 15µM for short-term or 12µM for long-term exposure). This correlates with EGFR activation following short-term or prolonged cisplatin treatment through the secretion of EGFR ligands. This activation of EGFR is concomitant to the decrease in other receptor tyrosine kinases phosphorylation including Met. Conclusions: The sensitivity of EGFR wild-type lung cancer cells to erlotinib in vitro is enhanced by cisplatin pretreatment. We identified potential markers of this sensitization, namely EGFR ligands, which serum level might be predicitive of the optimal efficiency of EGFR TKI. In vivo validation of these markers is under investigation. The concomitant decrease in other receptor tyrosine kinases phosphorylation suggests that the targeting of other receptor tyrosine kinases might potentiate EGFR TKI efficiency.

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Impact of HER2 aberrations on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS STUDY subset analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9056 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9056-9056 ◽

Cited By ~ 1

Author(s):

Hiroe Kayatani ◽

Keisuke Aoe ◽

Kadoaki Ohashi ◽

Hiroshige Yoshioka ◽

Akihiro Bessho ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Her2 Protein ◽

Epidermal Growth ◽

Tki Treatment ◽

Egfr Mutant ◽

Egfr Mutated ◽

Egfr Tki ◽

Egfr Tkis

9056 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]

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ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non–Small Cell Lung Cancer

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-19-2321 ◽

2020 ◽

Vol 26 (9) ◽

pp. 2244-2256 ◽

Cited By ~ 5

Author(s):

Naoko Okura ◽

Naoya Nishioka ◽

Tadaaki Yamada ◽

Hirokazu Taniguchi ◽

Keiko Tanimura ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Adaptive Resistance ◽

Tki Treatment ◽

Egfr Mutated ◽

Egfr Tki

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Abstract 1586: Evaluation of AXL expression on circulating tumor cells from EGFR mutated lung cancer patients who have relapsed after the EGFR TKI treatment

10.1158/1538-7445.am2018-1586 ◽

2018 ◽

Cited By ~ 1

Author(s):

Young Hun Kim ◽

Myoung Shin Kim ◽

Jun Sup Lee ◽

Hyun Kyung Lee ◽

Jae Hyuk Lee ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Lung Cancer Patients ◽

Tki Treatment ◽

Egfr Mutated ◽

Egfr Tki

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Non-classic EGFR mutations in a cohort of Dutch EGFR-mutated NSCLC patients and outcomes following EGFR-TKI treatment

British Journal of Cancer ◽

10.1038/bjc.2016.372 ◽

2016 ◽

Vol 115 (12) ◽

pp. 1504-1512 ◽

Cited By ~ 20

Author(s):

J L Kuiper ◽

S M S Hashemi ◽

E Thunnissen ◽

P J F Snijders ◽

K Grünberg ◽

...

Keyword(s):

Egfr Mutations ◽

Tki Treatment ◽

Nsclc Patients ◽

Egfr Mutated ◽

Egfr Tki

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Dynamic Evaluation of Circulating miRNA Profile in EGFR-Mutated NSCLC Patients Treated with EGFR-TKIs

Cells ◽

10.3390/cells10061520 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1520

Author(s):

Alessandro Leonetti ◽

Mjriam Capula ◽

Roberta Minari ◽

Giulia Mazzaschi ◽

Alessandro Gregori ◽

...

Keyword(s):

Statistical Significance ◽

Dynamic Change ◽

Complete Response ◽

Dynamic Evaluation ◽

Tki Treatment ◽

Nsclc Patients ◽

Egfr Mutated ◽

Egfr Tki ◽

Egfr Tkis

Background: Resistance to EGFR-TKIs constitutes a major challenge for the management of EGFR-mutated NSCLC, and recent evidence suggests that deregulation of specific microRNAs (miRNAs) may influence resistance to targeted agents. In this retrospective study, we explored the role of specific plasmatic miRNAs (miR-21, miR-27a and miR-181a) as a surrogate for predicting EGFR-TKI performance in EGFR-mutated NSCLC patients. Methods: Plasma samples of 39 advanced EGFR-mutated NSCLC patients treated with EGFR-TKIs were collected at different points in time and miRNA levels were assessed by RT-PCR. Results: Higher basal values of miR-21 were reported in patients who achieved a partial/complete response (PR/CR) compared to those with stability/progression of disease (SD/PD) (p = 0.011). Along the same line, patients who experienced a clinical benefit lasting at least six months displayed higher basal levels of circulating miR-21 (p = 0.039). However, dynamic evaluation of miRNA values after two months from the start of EGFR-TKI treatment showed that patients who experienced SD had an increase in miR-21 levels (Fold Change [FC] = 2.6) compared to patients achieving PR/CR (p = 0.029). The same tendency was observed for miR-27a (FC = 3.1) and miR-181a (FC = 2.0), although without reaching statistical significance. Remarkably, preclinical studies showed an increase in miR-21 levels in NSCLC cells that became resistant after exposure to EGFR-TKIs. Conclusions: Our study provides interesting insights on the role of circulating miRNAs, in particular miR-21, and their dynamic change over time in predicting EGFR-TKI response in EGFR-mutated NSCLC.

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Tyrosine kinase inhibitors (TKI) treatment of non-small cell lung cancer (NSCLC) patients (p) based on EGFR mutations (m) status in serum only.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19088 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e19088-e19088

Author(s):

Laia Capdevila ◽

Enric Carcereny ◽

Itziar de Aguirre ◽

Sara Cros ◽

Cristina Queralt ◽

...

Keyword(s):

Kinase Inhibitors ◽

Complete Response ◽

Phase Iii ◽

Egfr Mutations ◽

Molecular Alterations ◽

Former Smokers ◽

Tki Treatment ◽

Ecog Ps ◽

Egfr Mutated ◽

Egfr Tki

e19088 Background: Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy. However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless, so far, no data exists for NSCLC p treated according to EGFR m status in serum alone. Methods: We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue. We analyzed p treated with an EGFR TKI for whom EGFR m status was known in serum only (status in tissue unknown due to insufficient material). At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters: PFS, ORR and overall survival (OS). EGFR m analysis was performed in cell free circulating DNA (cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit. Results: 9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo). Conclusions: Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.

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