Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation

Florence Choo, Igor Odintsov, Kevin Nusser, Katelyn S. Nicholson, Lara Davis, Christopher L. Corless, Linda Stork, Romel Somwar, Marc Ladanyi, Jessica L. Davis, Monika A. Davare

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 newpatient-derived ssRMS cell lineOHSU-SARC001, harboring MYOD1 L122R as well as alterations in PTEN, PIK3CA, and GNAS.We explored the functional impact of these aberrations on oncogenic signalingwith 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 ofmolecularly targeted PI3K/AKT/mTORand RAS/MAPK inhibitors to block oncogenic signaling and suppress the growth of OHSU-SARC001 cells. Dual PI3K/mTOR (LY3023414, bimiralisib) andAKT 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 theimportance of utilizingpatient-derivedmodels to assessmolecularly targetable treatments and their potential as future treatment options.

Original languageEnglish (US)
Article numbera006140
JournalCold Spring Harbor Molecular Case Studies
Issue number1
StatePublished - Jan 2022

ASJC Scopus subject areas

  • Medicine(all)


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