RMC-5552 / Revolution Medicines - LARVOL DELTA

Critical role for the TGF-β1/mTORC1 signaling axis in defining the transcriptional identity of CTHRC1+ pathologic fibroblasts. (PubMed, Sci Adv) - "Using the selective mTORC1 inhibitor RMC-5552, we confirm a causal role for mTORC1 in promoting the acquisition of the collagen-high, CTHRC1+ phenotype in response to TGF-β1 stimulation in fibroblasts derived from patients with either IPF or lung adenocarcinoma. We conclude that mTORC1 plays a key role in shaping the transcriptional identity of these fibroblasts, with implications for therapeutic inhibition of mTORC1 in fibrosis and cancer."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CTHRC1 • EIF4EBP1 • TGFB1

The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial. (PubMed, Clin Cancer Res) - P1 | "The success of TM-mediated prophylaxis and the clearance of selected variants in ctDNA are concordant with selective, on-mechanism, antitumor activity following RMC-5552 treatment. These data show that RMC-5552, the first bi-steric mTORC1-selective inhibitor in the clinic, is active at tolerable doses, and that selective inhibition of mTORC1 alleviates mTORC2-mediated hyperglycemia, overcoming a key limitation of prior mTOR inhibitors."

Journal • P1 data • Diabetes • Endometrial Cancer • Fatigue • Mucositis • Oncology • Solid Tumor • Stomatitis • EIF4EBP1 • PIK3CA • PTEN

Cabozantinib and RMC-5552 synergistically inhibit translation and OXPHOS in clear cell renal cell carcinoma (EACR 2026) - "We identified a novel synergistic treatment combination for ccRCC, in vitro and in vivo, that affects cells proliferation by perturbing cellular metabolic status. This combination appears highly promising and may ultimately contribute to improve therapeutic management of ccRCC patients, with potential extension to other cabozantinib-treated cancers, such as liver cancer (HCC)."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Liver Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EIF4EBP1

Synergistic preclinical activity of dual CDK4/6 and mTORC1 inhibition in translocation renal cell carcinoma (AACR 2026) - "Pharmacological inhibition of CDK4/6 activity using palbociclib or abemaciclib, causes cell cycle arrest which was also recapitulated upon genetic knockout of CDK4/6 using CRISPR-Cas9. The combination of palbociclib and RMC-5552 in a tRCC xenograft model showed greater efficacy than either single agent while also being well-tolerated.Conclusions- Our work suggests that combined inhibition of CDK4/6 and mTORC1 activity has therapeutic potential in tRCC. This work may offer rationale for molecularly directed therapies in tRCC, which currently lacks any standard of care."

Preclinical • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CCND1 • TFE3

Oncogenic KRAS mutations drive estrogen independence and induce targetable vulnerabilities in treatment-resistant ER+ breast cancer (AACR 2026) - "In both cell lines, KRASG12V drove resistance to estrogen deprivation (mimicking aromatase inhibitor treatment) and total ER blockade (estrogen deprivation + Fulvestrant), while parental cell growth stalled...Treatment with the RAS(ON) multi-selective inhibitor daraxonrasib completely abrogated the estrogen-independent proliferation of KRASG12V cells. To determine signaling dependencies downstream of KRASG12V we treated cells with the mTORC1-selective inhibitor RMC-5552 (mTORC1i) or the ERK1/2 inhibitor ulixertinib (ERKi)...We are actively investigating the underlying mechanisms and applying CRISPR knockout screens and RNA-seq to identify other vulnerabilities. Given the recent surge of clinically viable RAS inhibitors, these findings may inform new combination strategies for a highly refractory subset of ER+ breast cancer."

Late-breaking abstract • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HRAS • KRAS • NF1 • NRAS

RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: Nicholas Butowski | N=48 ➔ 7 | Trial completion date: Apr 2030 ➔ Dec 2025 | Recruiting ➔ Terminated | Trial primary completion date: Apr 2030 ➔ Dec 2025; Drug no longer provided by sponsor

Enrollment change • Monotherapy • Trial completion date • Trial primary completion date • Trial termination • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EIF4E • EIF4EBP1 • MIB1

A PIK3CA-driven mouse model of metaplastic breast carcinoma to assess potential therapeutic strategies (AACR 2024) - "In addition, we generated an everolimus resistant cell line following chronic drug exposure in vitro (MMTV-102 Par res). Both cellular models were tested for their sensitivity to the next-generation mTORC1 inhibitor RMC-5552 by proliferation and clonogenic assays...Tumors derived from our model are sensitive to PI3Kα and mTORC1 inhibitors, but eventually develop resistance to these agents. The use of next-generation mTORC1 inhibitors can overcome resistance in some cases, providing a rationale for their implementation in the treatment of patients with MBC."

Preclinical • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1S1 • ER • HER-2 • PGR • PIK3CA

The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer (AACR 2024) - "Disruption of this pathway using either an AKT inhibitor or mTORC1-specific inhibitor (RMC-6272, a preclinical tool compound representative of the clinical candidate RMC-5552) led to a greater reduction in transformation and proliferation in a KRASG12D-driven lung initiation model compared to the KRASG12C counterpart. Inhibiting the PI3K-AKT-mTOR axis alongside KRASG12D inhibition (MRTX1133) induced a robust, synergistic apoptotic response in KRASG12D tumor cell lines of varying sensitivity to KRASG12D inhibition alone, highlighting a potential combinatorial approach to override intrinsic resistance to KRASG12D inhibitors. Our preclinical data identify treatment vulnerabilities and suggest patient selection strategies for combination approaches that should be i) contextualized to individual RAS mutants, and ii) tailored to their downstream signaling programs."

Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Exploiting CDK4/6-mTORC1 dependency reveals synergistic therapeutic potential in translocation renal cell carcinoma* (AACR-Kidney 2026) - "Pharmacologic CDK4/6 blockade with palbociclib or abemaciclib induced cell-cycle arrest, replicating the effects of CRISPR-Cas9 CDK4/6 deletion, and produced sustained reductions in proliferation, with rapid regrowth upon drug withdrawal...Combined palbociclib and RMC-5552 treatment synergistically impaired tRCC viability and heightened apoptotic signaling in vitro. In xenograft models, the combination achieved superior tumor suppression over monotherapy with individual agents along with favorable tolerability.Conclusions-Our findings reveal a mechanistic dependency on coordinated CDK4/6 and mTORC1 signaling in tRCC and concurrent inhibition of CDK4/6 and mTORC1 represents a promising therapeutic approach for tRCC. This strategy supports the development of molecularly informed treatments for a cancer subtype that currently lacks a defined standard of care."

Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CCND1 • CDK4 • TFE3

Coexistent PTEN and PIK3CA alterations hyperactivate mTORC1 signaling in endometrial cancers and cause their selective sensitivity to mTORC1 inhibition. (PubMed, bioRxiv) - "These findings are consistent with a phase I trial of bi-steric mTORC1 inhibitor RMC-5552, showing anti-tumor activity in patients with EC. PDXs with KRAS co-mutations regrew after RMC-6272 treatment, which was prevented by the addition of the RAS(ON) multi-selective inhibitor RMC-7977...Single mutant tumors are sensitive to PI3K inhibition but those with both mutations are insensitive to PI3K or AKT inhibition but are exquisitely dependent on mTORC1 kinase. This provides strong preclinical rationale for targeting mTORC1, alone or combined with RAS inhibition (in RAS co-mutant tumors), as an effective therapeutic strategy."

Journal • Endometrial Cancer • Oncology • Solid Tumor • KRAS • PIK3CA • PTEN

Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma. (SNO 2025) - "We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib...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...Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone...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."

Brain Cancer • Glioblastoma • Solid Tumor • NF1

Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma. (WFNOS 2025) - "We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib...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...Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone...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."

Brain Cancer • Glioblastoma • Solid Tumor • NF1

RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Nicholas Butowski | Suspended ➔ Recruiting

Enrollment open • Monotherapy • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EIF4E • EIF4EBP1 • MIB1

Portoghese lecture: Advancing bRo5 chemical matter to the clinic (ACS-Fall 2025) - P1, P3 | "Using this approach, we developed the investigational agent, RMC-5552, a bi-steric inhibitor that is mTORC1-selective via its FKBP12-binding moiety and potently inhibits phosphorylation of the 4EBP1 tumor suppressor via a linked ATP-competitive moiety. The RASG12D mutation increases the abundance of RASG12D(ON) and occurs commonly in multiple tumor histotypes, including RAS mutant pancreatic, colorectal, and non-small cell lung cancers. We are exploring two approaches for the treatment of RASG12D-addicted cancers, including the investigational agents daraxonrasib (RMC-6236), an oral, RAS(ON) multi-selective inhibitor currently in Phase III (NCT06625320), and zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, covalent inhibitor currently in Phase I/Ib (NCT06040541) as a monotherapy and in combination with daraxonrasib."

Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EIF4EBP1

Extracellular Matrix and Fibroblast Activation in Lymphangioleiomyomatosis. (PubMed, Am J Respir Cell Mol Biol) - "This demonstrates that mTORC1-driven 4E-BP1/eIF4E rapamycin-insensitive translational control overrides transcriptional control of ECM genes. Inhibition by RMC-5552 of ECM and fibroblast activation may result in destruction of CSC-like LAM cells and provide more enduring therapy for LAM patients."

Journal • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • COL1A1 • COL6A1 • CTHRC1 • EIF4E • EIF4EBP1 • TGFB1

RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=48 | Suspended | Sponsor: Nicholas Butowski | Trial completion date: Dec 2025 ➔ Apr 2030 | Trial primary completion date: Dec 2025 ➔ Apr 2030

Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • EIF4E • EIF4EBP1 • MIB1

Targeting the MYC oncogene with a selective bi-steric mTORC1 inhibitor elicits tumor regression in MYC-driven cancers. (PubMed, Cell Chem Biol) - "RMC-5552 exhibits anti-tumor activity in human patient-derived xenografts models harboring genomic MYC amplifications and reduces MYC protein levels in vivo. Furthermore, bi-steric mTORC1-selective inhibitors enhance the efficacy of immune checkpoint blockade, leading to tumor regression."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • EIF4EBP1

Dual Inhibition of CDK4/6 and mTORC1 Establishes a Preclinical Strategy for Translocation Renal Cell Carcinoma. (PubMed, bioRxiv) - "We demonstrate that combining the CDK4/6 inhibitor palbociclib with the mTORC1-selective inhibitor RMC-5552 synergistically inhibits the growth of tRCC cells in vitro and of tRCC xenografts in vivo , where the combination is well-tolerated. This proof-of-concept study provides preclinical evidence supporting CDK4/6 inhibitor-based combination regimens tailored to tRCC biology, offering a foundation for future clinical studies in tRCC, which currently has no clear standard of care."

Journal • Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CCND1 • CDK4 • TFE3

Preclinical efficacy of combined CDK4/6 and mTORC1 inhibition in translocation renal cell carcinoma (KCRS 2025) - "Pharmacological inhibition of CDK4/6 activity using palbociclib or abemaciclib, causes cell cycle arrest which was also recapitulated upon genetic knockout of CDK4/6 using CRISPR-Cas9...Combined treatment with the CDK4/6 inhibitor, palbociclib, and RMC-5552 resulted in synergistic suppression of tRCC cell viability and increased markers of apoptosis in vitro...Conclusions Our work suggests that combined inhibition of CDK4/6 and mTORC1 activity has therapeutic potential in tRCC. This work may offer rationale for molecularly directed therapies in tRCC, which currently lacks any standard of care."

Preclinical • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CCND1 • TFE3

Extracellular Matrix Proteins and Signaling in Lymphangioleiomyomatosis (ATS 2025) - "This abstract is funded by: R01HL151467, RO1HL158737, UO1HL131022, DOD TSCRP W81XWH2210503 Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease caused by hyperactivation of the mechanistic target of rapamycin 1 (mTORC1) growth pathway in a subset of lung mesenchymal cells. The WNT/β-catenin transcription inhibitor C82 prevented TGFβ induction of COL6A1, COL1A1 and CTHRC1. Our research highlights a protective role for ECM in LAM lesions and supports the hypothesis that the bisteric mTORC1-selective inhibitor RMC-5552 or inhibition of Wnt/β-catenin signaling may offer novel therapeutic benefits to LAM patients."

Fibrosis • Pulmonary Disease • Solid Tumor • COL1A1 • COL6A1 • CTHRC1 • TGFB1

RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=48 | Suspended | Sponsor: Nicholas Butowski | Recruiting ➔ Suspended

Monotherapy • Trial suspension • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • EIF4E • EIF4EBP1 • MIB1

Dose Escalation of RMC-5552 Monotherapy in Relapsed/Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=58 | Completed | Sponsor: Revolution Medicines, Inc. | Active, not recruiting ➔ Completed | N=108 ➔ 58

Enrollment change • Monotherapy • Trial completion • Solid Tumor

The Bi-Steric Inhibitor RMC-5552 Reduces mTORC1 Signaling and Growth in Lymphangioleiomyomatosis. (PubMed, Am J Respir Cell Mol Biol) - "Rapamycin inhibition of LAF growth was rapidly reversed, but RMC-5552 inhibition was more durable. RMC-5552, through its potential to eradicate LAM cancer SLS cells, may have therapeutic benefit in LAM and other diseases with mTORC1 hyperactivity."

Journal • Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • EIF4E • EIF4EBP1 • TSC1

Activity of CDK4/6 inhibitors in translocation renal cell carcinoma (EORTC-NCI-AACR 2024) - "Palbociclib or abemaciclib treatment in tRCC cell lines also showed increased -galactosidase activity, an indicator of senescence but resulted in minimal apoptosis...Combination treatment with palbociclib and RMC-5552 shows enhanced suppression of clonogenic capacity relative to single-agent treatment, results in lack of cell regrowth after drug washout, and leads to an increase in apoptosis...Conclusions- Our work suggests that CDK4/6 inhibitors and CDK4/6-mTORC1 inhibitor combinations may be active in tRCC. This work may offer rationale for molecularly-directed therapies in tRCC, which currently lacks any standard of care."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CDKN2A • PI3K • RB1 • TFE3

RMC-5552 Monotherapy in Adult Subjects With Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Nicholas Butowski | Active, not recruiting ➔ Recruiting

Enrollment open • Monotherapy • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor