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 e...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/58204 |
| _version_ | 1811181027110944768 |
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| author | Patricia L Theard Erin Sheffels Nancy E Sealover Amanda J Linke David J Pratico Robert L Kortum |
| author_facet | Patricia L Theard Erin Sheffels Nancy E Sealover Amanda J Linke David J Pratico Robert L Kortum |
| author_sort | Patricia L Theard |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T09:11:27Z |
| format | Article |
| id | doaj.art-4511fbc1380749d192e9b877015f7dca |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:11:27Z |
| publishDate | 2020-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-4511fbc1380749d192e9b877015f7dca2022-12-22T04:32:29ZengeLife Sciences Publications LtdeLife2050-084X2020-09-01910.7554/eLife.58204Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancerPatricia L Theard0Erin Sheffels1Nancy E Sealover2Amanda J Linke3David J Pratico4Robert L Kortum5https://orcid.org/0000-0002-1634-4882Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, United StatesDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, United StatesDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, United StatesDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, United StatesDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, United StatesDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, United StatesDrug 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.https://elifesciences.org/articles/58204spheroidsson of sevenlesssynergylung adenocarcinoma |
| spellingShingle | Patricia L Theard Erin Sheffels Nancy E Sealover Amanda J Linke David J Pratico Robert L Kortum Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer eLife spheroids son of sevenless synergy lung adenocarcinoma |
| title | Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer |
| title_full | Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer |
| title_fullStr | Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer |
| title_full_unstemmed | Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer |
| title_short | Marked synergy by vertical inhibition of EGFR signaling in NSCLC spheroids shows SOS1 is a therapeutic target in EGFR-mutated cancer |
| title_sort | marked synergy by vertical inhibition of egfr signaling in nsclc spheroids shows sos1 is a therapeutic target in egfr mutated cancer |
| topic | spheroids son of sevenless synergy lung adenocarcinoma |
| url | https://elifesciences.org/articles/58204 |
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