Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas
<i>KRAS</i> mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/12/9/1402 |
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| author | Elisa Baldelli Emna El Gazzah John Conor Moran Kimberley A. Hodge Zarko Manojlovic Rania Bassiouni John D. Carpten Vienna Ludovini Sara Baglivo Lucio Crinò Fortunato Bianconi Ting Dong Jeremy Loffredo Emanuel F. Petricoin Mariaelena Pierobon |
| author_facet | Elisa Baldelli Emna El Gazzah John Conor Moran Kimberley A. Hodge Zarko Manojlovic Rania Bassiouni John D. Carpten Vienna Ludovini Sara Baglivo Lucio Crinò Fortunato Bianconi Ting Dong Jeremy Loffredo Emanuel F. Petricoin Mariaelena Pierobon |
| author_sort | Elisa Baldelli |
| collection | DOAJ |
| description | <i>KRAS</i> mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) <i>KRAS</i> on druggable targets can uncover new vulnerabilities for the treatment of <i>KRAS</i> mutant lung adenocarcinomas. Using commercially available <i>KRAS</i> mutant lung adenocarcinoma cell lines, we explored the influence of WT <i>KRAS</i> on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the <i>KRAS</i> WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the <i>KRAS</i> WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT <i>KRAS</i> impacts on signaling events and druggable targets in <i>KRAS</i> mutant lung adenocarcinomas. |
| first_indexed | 2024-03-10T07:39:14Z |
| format | Article |
| id | doaj.art-f9eecad718b64cdf953c0e9b96836030 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T07:39:14Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-f9eecad718b64cdf953c0e9b968360302023-11-22T13:14:32ZengMDPI AGGenes2073-44252021-09-01129140210.3390/genes12091402Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung AdenocarcinomasElisa Baldelli0Emna El Gazzah1John Conor Moran2Kimberley A. Hodge3Zarko Manojlovic4Rania Bassiouni5John D. Carpten6Vienna Ludovini7Sara Baglivo8Lucio Crinò9Fortunato Bianconi10Ting Dong11Jeremy Loffredo12Emanuel F. Petricoin13Mariaelena Pierobon14Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USACenter for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USACenter for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USACenter for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USAKeck School of Medicine, University of Southern California, Los Angeles, CA 90033, USAKeck School of Medicine, University of Southern California, Los Angeles, CA 90033, USAKeck School of Medicine, University of Southern California, Los Angeles, CA 90033, USADivision of Medical Oncology, S. Maria della Misericordia Hospital, 06156 Perugia, ItalyDivision of Medical Oncology, S. Maria della Misericordia Hospital, 06156 Perugia, ItalyDepartment of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, ItalyIndependent Researcher, Belvedere 44, Montefalco, 06036 Perugia, ItalyCenter for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USACenter for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USACenter for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USACenter for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA<i>KRAS</i> mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) <i>KRAS</i> on druggable targets can uncover new vulnerabilities for the treatment of <i>KRAS</i> mutant lung adenocarcinomas. Using commercially available <i>KRAS</i> mutant lung adenocarcinoma cell lines, we explored the influence of WT <i>KRAS</i> on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the <i>KRAS</i> WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the <i>KRAS</i> WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT <i>KRAS</i> impacts on signaling events and druggable targets in <i>KRAS</i> mutant lung adenocarcinomas.https://www.mdpi.com/2073-4425/12/9/1402non-small cell lung cancerKRASzygositydrug targetreverse-phase protein microarray |
| spellingShingle | Elisa Baldelli Emna El Gazzah John Conor Moran Kimberley A. Hodge Zarko Manojlovic Rania Bassiouni John D. Carpten Vienna Ludovini Sara Baglivo Lucio Crinò Fortunato Bianconi Ting Dong Jeremy Loffredo Emanuel F. Petricoin Mariaelena Pierobon Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas Genes non-small cell lung cancer KRAS zygosity drug target reverse-phase protein microarray |
| title | Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas |
| title_full | Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas |
| title_fullStr | Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas |
| title_full_unstemmed | Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas |
| title_short | Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas |
| title_sort | wild type kras allele effects on druggable targets in kras mutant lung adenocarcinomas |
| topic | non-small cell lung cancer KRAS zygosity drug target reverse-phase protein microarray |
| url | https://www.mdpi.com/2073-4425/12/9/1402 |
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