East, Michael P, Olivares-Quintero, J Felix, Okumu, Denis O, Mott, Kevin R, Sprung, Robert W, Whitman, Austin A, Joisa, Chinmaya U, Chen, Xin, Zhang, Qiang, Erdmann-Gilmore, Petra, Mi, Yiling, Malone, James P, Bhatia, Sonam, McCabe, Ian C, Xu, Yi, Sutcliffe, Matthew D, Spears, Patricia A, Zawistowski, Jon S, Perou, Charles M, Earp, H Shelton, Carey, Lisa A, Yeh, Jen Jen, Spector, David L, Stover, Daniel, Gomez, Shawn M, Spanheimer, Philip M, Townsend, R Reid, Johnson, Gary L (September 2026) Vulnerability of triple negative breast cancer to daraxonrasib pan-RAS(on) inhibition. bioRxiv. ISSN 2692-8205 (Submitted)
Abstract
Triple-Negative Breast Cancer (TNBC) is a clinical subtype where aberrant expression of receptor tyrosine kinases (RTKs) leads to the activation of the RAS-RAF-MEK-ERK pathway contributing to tumor progression. Therapies targeting components of the RAF-MEK-ERK pathway in TNBC have been disappointing due to rapid onset of adaptive reprogramming of the RTK landscape leading to pathway reactivation. To overcome the dynamic heterogeneity of RTK expression and their convergence in activating RAS, treatment with the pan-RAS(on) inhibitor daraxonrasib (RMC-6236), which inhibits RAS-GTP regulation of RAF kinases, inhibited proliferation independent of TNBC kinotype or oncogenic RAS mutation in three of four TNBC cell lines in vitro and two patient-derived TNBC xenografts in mice. Daraxonrasib in combination with the MEK inhibitor trametinib prevented reactivation of the RAF-MEK-ERK pathway observed with each inhibitor alone and further enhanced inhibition of tumor growth in TNBC cell lines and xenografts. Inhibiting pan-RAS(on) RAS-GTP with daraxonrasib, alone or in combination with a MEK inhibitor, provides a new strategy for the treatment of TNBC that inhibits RTK activation of the RAS-RAF-MEK-ERK pathway and tumor proliferation.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Spector lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 18 September 2026 |
| Date Deposited: | 28 Sep 2026 18:45 |
| Last Modified: | 28 Sep 2026 18:45 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42328 |
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