Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models

Corte, Carminia Maria Della; Ciaramella, Vincenza; Cardone, Claudia; Monica, Silvia La; Alfieri, Roberta; Petronini, Pier Giorgio; Malapelle, Umberto; Vigliar, Elena; Pepe, Francesco; Troncone, Giancarlo; Castellone, Maria Domenica; Troiani, Teresa; Martinelli, Erika

doi:10.1016/j.jtho.2018.02.025

Cited by 32 publications

(27 citation statements)

References 35 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Osimertinib resistant can occur via oncogenic shift to alternative RTKs including c-MET (11), HER2 and/or HER3 (7-9), IGF1R (12), and AXL (13)(14)(15)(16). The variety of RTK bypass pathways that can lead to osimertinib resistance suggests that broad inhibition of RTK signaling may be a more effective therapeutic strategy than any individual RTK inhibitor to limit Combining osimertinib with a MEK inhibitor can enhance osimertinib efficacy (10,17,20,56,57) and Phase II clinical trials are currently underway to assess combining osimertinib with the MEK inhibitor selumetinib in EGFR-mutated NSCLC (NCT03392246), although resistance to combined osimertinib and MEK inhibition still occurs (17). In a recent study designed to understand resistance to combined osimertinib and MEK inhibition, Kurppa et al (2020) show that combining osimertinib with the MEK inhibitor trametinib results in EGFRmutated cells entering a senescent state that is dependent on the activation of the Hippo pathway effector YAP and its transcription factor binding partner TEAD (58).…”

Section: Discussionmentioning

confidence: 99%

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

Theard

Sheffels

Sealover

et al. 2020

Preprint

View full text Add to dashboard Cite

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.of RAS, co-targeting intermediates of the RAF/MEK/ERK and PI3K/AKT pathways enhances of osimertinib effectiveness, however, signaling through the uninhibited effector pathway may drive resistance (17)(18)(19)(20). Thus, it may be important for therapeutic combinations including osimertinib to stifle all downstream RTK/RAS signaling to be effective.Recent studies suggest that pharmacologic assessments of targeted therapeutics should be performed under 3D culture conditions rather than in 2D adherent cultures (21,22). 3D spheroids show altered growth characteristics, changes in cell surface proteins, altered metabolism, changes in activation of signaling pathways or altered responses to targeted pathway inhibitors, and are more resistant to drug-induced apoptosis compared to 2D adherent cultures signaling (23-26). These differences may be particularly relevant in EGFR-mutated NSCLC. EGFR-mutated cells show differential RTK expression and phosphorylation in 3D versus 2Dconditions (27). Further, EGFR-mutated cells respond more robustly to first-generation EGFR-TKIs in 3D cultures, and these responses more closely resemble responses seen in vivo (28).These data highlight the need for pharmacologic assessment of therapeutics designed to treat EGFR-mutated NSCLC under 3D culture conditions. The ubiquitously expressed RasGEFs (guanine nucleotide exchange factors) SOS1 and SOS2 (son of sevenless 1 and 2) are common signaling intermediates of RTK-mediated RAS activation. Although not initially considered as drug targets because of the low oncogenic potential of SOS (29), there has been renewed interest in SOS proteins as therapeutic targets for cancer treatment. We and others have shown that SOS1 and SOS2 may be important therapeutic targets in KRAS-mutated cancer cells (30-32), and a specific SOS1 inhibitor (BAY-293) has recently been identified (33). Here, we investigate SOS1 and SOS2 as potential therapeutic targets in EGFR-mutated l...

show abstract

Section: Discussionmentioning

confidence: 99%

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

Theard

Sheffels

Sealover

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This finding was consistent with a previous report stating that Cet was an efficient tumor-targeting moiety by binding to EGFR excessively expressed on the surface of colorectal cancer cells. 33…”

Section: Cellular Uptakementioning

confidence: 99%

<p>Combined Therapeutic Effects of <sup>131</sup>I-Labeled and 5Fu-Loaded Multifunctional Nanoparticles in Colorectal Cancer</p>

Wu¹,

Zhu²,

Zhuang³

et al. 2020

IJN

View full text Add to dashboard Cite

Background: Owing to its combined effects, the co-delivery of different therapeutics is a promising option for the treatment of cancer. In the present study, tumor-targeting poly (ethylene glycol)-poly(lactic acid) (PEG-PLA) nanoparticles were developed for the transportation of two molecules, namely chemotherapeutic drug 5-fluorouracil (5Fu) and radionuclide iodine-131 (131 I), in a single platform. Methods: The obtained nanoparticles (Cetuximab [Cet]-PEG-PLA-5Fu-131 I) were spherical (diameter approximately 110 nm) and pH-sensitive. The targeting effect of nanoparticles via Cet was confirmed in colorectal cancer cells using a fluorescent assay. The combined effects of Cet-PEG-PLA-5Fu-131 I on cell viability and apoptosis were evaluated in colorectal cancer cells by Cell Counting Kit-8 and flow cytometry assays. Results: Blank nanoparticles (Cet-PEG-PLA) showed good biocompatibility, and Cet-PEG-PLA-5Fu-131 I nanoparticles were the most effective in terms of inhibition of cell viability and induction of apoptosis compared with monotherapy using Cet-PEG-PLA-5Fu or Cet-PEG-PLA-131 I. In the xenograft mouse model, compared with using Cet-PEG-PLA-5Fu or Cet-PEG-PLA-131 I alone, Cet-PEG-PLA-5Fu-131 I nanoparticles exhibited prolonged circulation in the blood and accumulation in the tumor, thus resulting in enhanced antitumor efficacy. Additionally, combined radio-chemotherapy with Cet-PEG-PLA-5Fu-131 I nanoparticles was associated with smaller tumor sizes than monotherapy, revealing the superior antitumor effects of Cet-PEG-PLA-5Fu-131 I nanoparticles. These effects were further evidenced by histological and immunohistochemical analyses. Conclusion: The multifunctional Cet-PEG-PLA-5Fu-131 I nanoparticles are promising candidates for the co-delivery of 5Fu-mediated chemotherapy and 131 I-mediated radiotherapy.

show abstract

“…NSCLC cells with acquired resistance to EGFR TKIs have a high level of Smo expression, through Smo amplification [ 127 ]. Della-Corte et al used in vivo xenograft models of EGFR mutated NSCLC treated with third-generation EGFR TKI (osimertinib) in association with a Mek inhibitor (selumetinib) [ 128 ]. They showed that Shh pathway is involved in resistance to this combo treatment, and that inhibition of Shh pathway inhibits proliferation, cell migration, and invasive properties of ex vivo resistant cultured cells.…”

Section: Shh Pathway and Resistance To Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

Leprieur

Costantini

Ding

et al. 2018

IJMS

View full text Add to dashboard Cite

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.

show abstract

Antitumor Efficacy of Dual Blockade of EGFR Signaling by Osimertinib in Combination With Selumetinib or Cetuximab in Activated EGFR Human NCLC Tumor Models

Abstract: We showed that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated NCLC and that hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments.

Cited by 32 publications

References 35 publications

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

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

<p>Combined Therapeutic Effects of <sup>131</sup>I-Labeled and 5Fu-Loaded Multifunctional Nanoparticles in Colorectal Cancer</p>

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance

Contact Info

Product

Resources

About