Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation Journal Article
| Authors: | Choo, F.; Odinstov, I.; Nusser, K.; Nicholson, K. S.; Davis, L.; Corless, C. L.; Stork, L.; Somwar, R.; Ladanyi, M.; Davis, J. L.; Davare, M. A. |
| Article Title: | Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation |
| Abstract: | Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a rare subtype of rhabdomyosarcoma, commonly harboring a gain-of-function L122R mutation in the muscle-specific master transcription factor MYOD1. MYOD1-mutated ssRMS is almost invariably fatal, and development of novel therapeutic approaches based on the biology of the disease is urgently needed. MYOD1 L122R affects the DNA-binding domain and is believed to confer MYC-like properties to MYOD1, driving oncogenesis. Moreover, the majority of the MYOD1-mutated ssRMS harbor additional alterations activating the PI3K/AKT pathway. It is postulated that the PI3K/AKT pathway cooperates with MYOD1 L122R. To address this biological entity, we established and characterized a new patient-derived ssRMS cell line OHSU-SARC001, harboring MYOD1 L122R as well as alterations in PTEN, PIK3CA, and GNAS We explored the functional impact of these aberrations on oncogenic signaling with gain-of-function experiments in C2C12 murine muscle lineage cells. These data reveal that PIK3CAI459_T462del, the novel PIK3CA variant discovered in this patient specimen, is a constitutively active kinase, albeit to a lesser extent than PI3KCAE545K, a hotspot oncogenic mutation. Furthermore, we examined the effectiveness of molecularly targeted PI3K/AKT/mTOR and RAS/MAPK inhibitors to block oncogenic signaling and suppress the growth of OHSU-SARC001 cells. Dual PI3K/mTOR (LY3023414, bimiralisib) and AKT inhibitors (ipatasertib, afuresertib) induced dose-dependent reductions in cell growth. However, mTOR-selective inhibitors (everolimus, rapamycin) alone did not exert cytotoxic effects. The MEK1/2 inhibitor trametinib did not impact proliferation even at the highest doses tested. Our data suggest that molecularly targeted strategies may be effective in PI3K/AKT/mTOR-activated ssRMS. Taken together, these data highlight the importance of utilizing patient-derived models to assess molecularly targetable treatments and their potential as future treatment options. © 2022 Choo et al.; Published by Cold Spring Harbor Laboratory Press. |
| Keywords: | protein kinase b; adult; child; genetics; mutation; mouse; animal; animals; mice; transcription factor; cell line, tumor; phosphatidylinositol 3 kinase; transcription factors; oncogenes; oncogene; tumor cell line; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; pten phosphohydrolase; rhabdomyosarcoma; chromogranin; pten protein, human; myod protein; phosphatidylinositol 3-kinases; chromogranins; humans; human; stimulatory guanine nucleotide binding protein; gtp-binding protein alpha subunits, gs; gnas protein, human; pi3kca protein, human |
| Journal Title: | Cold Spring Harbor Molecular Case Studies |
| Volume: | 8 |
| Issue: | 1 |
| ISSN: | 2373-2873 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2022-01-01 |
| Start Page: | a006140 |
| Language: | English |
| DOI: | 10.1101/mcs.a006140 |
| PUBMED: | 35012940 |
| PROVIDER: | scopus |
| PMCID: | PMC8744497 |
| DOI/URL: | |
| Notes: | Article -- MSK author Igor Odintsov's last name is misspelled on the original publication -- Export Date: 1 March 2022 -- Source: Scopus |
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