EXTH-117. Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma Article Swipe

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Qi-Wen Fan , Jessica Koach , Kui Luo , Sydney D. Biscarri Clark , Sunil Reddy , Tomoko Ozawa , L. Wang , Hiroyuki Yoda , Matthew J. Sale , Frank McCormick , David R. Raleigh , W. Clay Gustafson , Mallika Singh , William A. Weiss ·

YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.1093/neuonc/noaf201.1450

We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib. RapaLink-1 showed increased efficacy compared to either parent inhibitor in orthotopic xenograft models for glioblastoma. The bitopic clinical derivative of this agent, RMC-5552 (Revolution Medicines/RevMed), is currently in a phase 1/2, UCSF SPORE-supported clinical trial in glioblastoma. We show that RMC-5552, RapaLink-1, and RevMed’s bioequivalent bitopic mTORC1 inhibitor RMC-6272 are cytostatic rather than cytotoxic preclinically. Here, identify combination strategies that drive cell death in glioblastoma. We screened RapaLink-1 and RMC-6272 in combination with a library of FDA-approved drugs in two glioblastoma lines. Among 2332 drugs, the clinical mitogen-activated protein kinase kinase (MEK) inhibitor trametinib was the most active agent in driving cytotoxicity in glioblastoma cells. Like trametinib, the MEK inhibitor selumetinib similarly cooperated with RMC-6272 to block proliferation and increase apoptosis in isogenic T98G glioblastoma lines knocked-down for NF1 compared to NF1 wild-type T98G cells. We rescued NF1 deficiency in NF1MT lines by expressing full length NF1. Combination therapy with trametinib and RMC-6272 drove apoptosis in both lines, more efficiently in NF1-rescued lines. RMC-6272 induced autophagy. Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone. RMC-6272 cooperated with trametinib in orthotopic xenografts of GBM43 in vivo, blocking proliferation, driving apoptosis and improving survival compared to either monotherapy. Biochemically, RMC-6272 cooperated with trametinib to block MAP kinase and mTORC1 signaling and to drive apoptosis in vivo. We conclude that bitopic inhibitors of mTORC1 cooperate with inhibitors of MEK to drive cytotoxicity in both NF1WT and NF1MT glioblastoma. Combining RMC-5552 and trametinib represents a translatable strategy to improve survival in patients with glioblastoma.

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Type: article
Language: en
Landing Page: https://doi.org/10.1093/neuonc/noaf201.1450
PDF: https://academic.oup.com/neuro-oncology/article-pdf/27/Supplement_5/v366/65256704/noaf201.1450.pdf
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DOI: https://doi.org/10.1093/neuonc/noaf201.1450

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Title: EXTH-117. Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma

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Language: en

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Publication year: 2025

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Publication date: 2025-11-01

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Authors: Qi-Wen Fan, Jessica Koach, Kui Luo, Sydney D. Biscarri Clark, Sunil Reddy, Tomoko Ozawa, L. Wang, Hiroyuki Yoda, Matthew J. Sale, Frank McCormick, David R. Raleigh, W. Clay Gustafson, Mallika Singh, William A. Weiss

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abstract_inverted_index.more	180
abstract_inverted_index.most	118
abstract_inverted_index.show	60
abstract_inverted_index.than	74
abstract_inverted_index.that	9, 61, 81, 248
abstract_inverted_index.this	42
abstract_inverted_index.tool	195
abstract_inverted_index.with	94, 135, 171, 208, 231, 254, 280
abstract_inverted_index.(MEK)	113
abstract_inverted_index.Among	104
abstract_inverted_index.GBM43	214
abstract_inverted_index.Here,	77
abstract_inverted_index.NF1MT	162, 265
abstract_inverted_index.NF1WT	263
abstract_inverted_index.agent	120
abstract_inverted_index.block	138, 234
abstract_inverted_index.death	84
abstract_inverted_index.drive	82, 242, 259
abstract_inverted_index.drove	175
abstract_inverted_index.drugs	99
abstract_inverted_index.lines	147, 163
abstract_inverted_index.links	10
abstract_inverted_index.phase	51
abstract_inverted_index.trial	56
abstract_inverted_index.vivo,	216
abstract_inverted_index.vivo.	245
abstract_inverted_index.active	119
abstract_inverted_index.agent,	43
abstract_inverted_index.alone.	205
abstract_inverted_index.cells.	126, 156
abstract_inverted_index.drugs,	106
abstract_inverted_index.either	28, 226
abstract_inverted_index.kinase	19, 111, 112, 236
abstract_inverted_index.length	167
abstract_inverted_index.lines,	179
abstract_inverted_index.lines.	103, 184
abstract_inverted_index.mTORC1	7, 13, 68, 238, 252
abstract_inverted_index.models	34
abstract_inverted_index.parent	29
abstract_inverted_index.rather	73
abstract_inverted_index.showed	23
abstract_inverted_index.bitopic	38, 67, 249
abstract_inverted_index.driving	122, 219
abstract_inverted_index.improve	276
abstract_inverted_index.induced	186
abstract_inverted_index.library	96
abstract_inverted_index.protein	110
abstract_inverted_index.rescued	158
abstract_inverted_index.therapy	170
abstract_inverted_index.Abstract	0
abstract_inverted_index.MRT68921	197
abstract_inverted_index.RMC-5552	44, 268
abstract_inverted_index.RMC-6272	70, 91, 136, 174, 185, 202, 206, 229
abstract_inverted_index.bisteric	6
abstract_inverted_index.blocking	217
abstract_inverted_index.clinical	39, 55, 108
abstract_inverted_index.compared	26, 151, 200, 224
abstract_inverted_index.conclude	247
abstract_inverted_index.efficacy	25
abstract_inverted_index.identify	78
abstract_inverted_index.increase	141
abstract_inverted_index.isogenic	144
abstract_inverted_index.patients	279
abstract_inverted_index.screened	88
abstract_inverted_index.strategy	274
abstract_inverted_index.survival	223, 277
abstract_inverted_index.Combining	188, 267
abstract_inverted_index.RMC-5552,	62
abstract_inverted_index.RMC-6272,	189
abstract_inverted_index.apoptosis	142, 176, 199, 220, 243
abstract_inverted_index.augmented	198
abstract_inverted_index.autophagy	193
abstract_inverted_index.cooperate	253
abstract_inverted_index.currently	48
abstract_inverted_index.cytotoxic	75
abstract_inverted_index.described	3
abstract_inverted_index.improving	222
abstract_inverted_index.increased	24
abstract_inverted_index.inhibitor	8, 14, 20, 30, 69, 114, 131, 196
abstract_inverted_index.rapamycin	15
abstract_inverted_index.signaling	239
abstract_inverted_index.similarly	133
abstract_inverted_index.wild-type	154
abstract_inverted_index.xenograft	33
abstract_inverted_index.RapaLink-1	22, 89
abstract_inverted_index.RevMed’s	65
abstract_inverted_index.allosteric	12
abstract_inverted_index.autophagy.	187
abstract_inverted_index.cooperated	134, 207, 230
abstract_inverted_index.cytostatic	72
abstract_inverted_index.deficiency	160
abstract_inverted_index.derivative	40
abstract_inverted_index.expressing	165
abstract_inverted_index.inhibitors	250, 255
abstract_inverted_index.orthotopic	32, 211
abstract_inverted_index.previously	2
abstract_inverted_index.represents	271
abstract_inverted_index.strategies	80
abstract_inverted_index.trametinib	115, 172, 190, 204, 209, 232, 270
abstract_inverted_index.xenografts	212
abstract_inverted_index.(Revolution	45
abstract_inverted_index.Combination	169
abstract_inverted_index.NF1-rescued	183
abstract_inverted_index.RapaLink-1,	4, 63
abstract_inverted_index.combination	79, 93
abstract_inverted_index.efficiently	181
abstract_inverted_index.selumetinib	132
abstract_inverted_index.trametinib,	128
abstract_inverted_index.FDA-approved	98
abstract_inverted_index.cytotoxicity	123, 260
abstract_inverted_index.glioblastoma	102, 125, 146
abstract_inverted_index.knocked-down	148
abstract_inverted_index.monotherapy.	227
abstract_inverted_index.translatable	273
abstract_inverted_index.bioequivalent	66
abstract_inverted_index.glioblastoma.	36, 58, 86, 266, 281
abstract_inverted_index.proliferation	139
abstract_inverted_index.sapanisertib.	21
abstract_inverted_index.Biochemically,	228
abstract_inverted_index.preclinically.	76
abstract_inverted_index.proliferation,	218
abstract_inverted_index.SPORE-supported	54
abstract_inverted_index.mitogen-activated	109
abstract_inverted_index.Medicines/RevMed),	46
cited_by_percentile_year
countries_distinct_count	1
institutions_distinct_count	14
citation_normalized_percentile