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Makhov P , Bychkov I , Faezov B , Deneka A , Kudinov A , Nicolas E , Brebion R , Avril E , Cai KQ , Kharin LV , Voloshin M , Frantsiyants E , Karnaukhov N , Kit OI , Topchu I , Fazliyeva R , Nikonova AS , Serebriiskii IG , Borghaei H , Edelman M , Dulaimi E , Golemis EA , Boumber Y
Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC)
Oncogenesis. 2021 Mar 15;10(3) :29
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Non-small cell lung cancer (NSCLC) has limited treatment options. Expression of the RNA-binding protein (RBP) Musashi-2 (MSI2) is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression, and drives NSCLC metastasis. We evaluated the mechanism of MSI2 action in NSCLC to gain therapeutically useful insights. Reverse phase protein array (RPPA) analysis of MSI2-depleted versus control Kras(LA1/+); Trp53(R172HΔG/+) NSCLC cell lines identified EGFR as a MSI2-regulated protein. MSI2 control of EGFR expression and activity in an NSCLC cell line panel was studied using RT-PCR, Western blots, and RNA immunoprecipitation. Functional consequences of MSI2 depletion were explored for cell growth and response to EGFR-targeting drugs, in vitro and in vivo. Expression relationships were validated using human tissue microarrays. MSI2 depletion significantly reduced EGFR protein expression, phosphorylation, or both. Comparison of protein and mRNA expression indicated a post-transcriptional activity of MSI2 in control of steady state levels of EGFR. RNA immunoprecipitation analysis demonstrated that MSI2 directly binds to EGFR mRNA, and sequence analysis predicted MSI2 binding sites in the murine and human EGFR mRNAs. MSI2 depletion selectively impaired cell proliferation in NSCLC cell lines with activating mutations of EGFR (EGFR(mut)). Further, depletion of MSI2 in combination with EGFR inhibitors such as erlotinib, afatinib, and osimertinib selectively reduced the growth of EGFR(mut) NSCLC cells and xenografts. EGFR and MSI2 were significantly co-expressed in EGFR(mut) human NSCLCs. These results define MSI2 as a direct regulator of EGFR protein expression, and suggest inhibition of MSI2 could be of clinical value in EGFR(mut) NSCLC.
Makhov, Petr Orcid: 0000-0002-8257-4782 Bychkov, Igor Orcid: 0000-0002-9275-5210 Faezov, Bulat Deneka, Alexander Kudinov, Alexander Nicolas, Emmanuelle Brebion, Rohan Orcid: 0000-0002-9039-4925 Avril, Eleanor Cai, Kathy Q Kharin, Leonid V Voloshin, Mark Orcid: 0000-0002-2302-3542 Frantsiyants, Elena Karnaukhov, Nikolay Kit, Oleg I Topchu, Iuliia Orcid: 0000-0001-9105-5207 Fazliyeva, Rushaniya Orcid: 0000-0002-6237-7802 Nikonova, Anna S Serebriiskii, Ilya G Borghaei, Hossein Edelman, Martin Dulaimi, Essel Golemis, Erica A Orcid: 0000-0003-3618-3673 Boumber, Yanis Orcid: 0000-0001-5003-248x R03 CA216173/CA/NCI NIH HHS/United States R01 CA218802/CA/NCI NIH HHS/United States R21 CA223394/CA/NCI NIH HHS/United States Journal Article United States Oncogenesis. 2021 Mar 15;10(3):29. doi: 10.1038/s41389-021-00317-y.