SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its “on” and “off” states. Disrupting the SOS1:KRAS G12C protein–protein interaction (PPI) can increase the proportion of GDP-loaded KRAS G12C , providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRAS G12C . In this report, we detail the design and discovery of MRTX0902—a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRAS G12C PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.
KRAS is the most frequently mutated oncogene in cancer and drives uncontrolled growth through hyperactivation of the MAPK pathway. Significant progress has been made in the past several years to directly target KRASG12C with the FDA approval of sotorasib and the reported clinical activity of adagrasib (MRTX849). Despite these remarkable breakthroughs, additional therapies that enhance the depth and duration of response to KRASG12C inhibitors provide the opportunity to build upon the initial progress. SOS proteins are guanine nucleotide exchange factors (GEFs) that transduce receptor tyrosine kinase (RTK) signaling from the cell surface and facilitate the activation of RAS family proteins. In addition, SOS1 is a target of negative feedback signaling following RAS-mediated activation of the RAF-MEK-ERK cascade. Thus, SOS proteins represent a significant therapeutic node that maintains RAS pathway equilibrium as well as oncogenic signaling dynamics. Here we highlight the discovery and preclinical evaluation of MRTX0902, a potent, selective, and orally bioavailable inhibitor of SOS1 presently in IND-enabling studies. A structure-based approach was used to identify a novel chemical series that disrupts the protein-protein interaction between SOS1 and KRAS, thereby preventing SOS1-mediated GTP-exchange on GDP-bound KRAS. Considering MRTX849 preferentially binds to inactive GDP-bound KRASG12C, targeting SOS1 in this genetic context increases the ability of MRTX849 to bind and inhibit KRASG12C. The combination of MRTX0902 with MRTX849 enhances the depth and durability of an anti-tumor response when compared to MRTX849 alone in pre-clinical KRASG12C tumor models. MRTX0902 augments additional targeted therapies across a variety of RAS-addicted tumors, indicating that SOS1 inhibition is effective against a broad spectrum of mutations within the MAPK pathway. Furthermore, drug-anchored CRISPR experiments with MRTX0902 and MRTX849 uncovered a previously underappreciated functional role of the SOS1 paralog, SOS2, in KRAS-addicted tumors. In addition to aiding in the understanding of SOS and RAS family signaling dynamics, these studies implicate SOS2 as a potential cancer drug target in the context of SOS1/KRASG12C inhibition. In summary, we have used a structure-based approach to discover a SOS1 inhibitor that augments the anti-tumor activity of MRTX849 and additional targeted MAPK pathway inhibitors. We anticipate our findings to translate into the clinic and make an impact in patients with RAS-addicted tumors. Citation Format: John M. Ketcham, Shilpi Khare, Niranjan Sudhakar, David M. Briere, Larry Yan, Jade Laguer, Laura Vegar, Darin Vanderpool, Jill Hallin, Lauren Hargis, Vickie Bowcut, David Lawson, Robin J. Gunn, Anthony Ivetac, Nicole C. Thomas, Barbara Saechao, Natalie Nguyen, Jeffrey Clarine, Lisa Rahbaek, Christopher R. Smith, Aaron C. Burns, Matthew A. Marx, James G. Christensen, Peter Olson, Jacob R. Haling. MRTX0902: A SOS1 inhibitor for therapeutic intervention of KRAS-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND02.
Osimertinib is a third generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recommended as a first line therapy in patients with advanced non-small lung cancer (NSCLC) characterized by EGFR activating mutations (exon 19 deletions and exon 21 L858R) and the resistance associated exon 20 T790M mutation, which is present in approximately 40-55% of patients following treatment with first generation EGFR-targeting inhibitors. Unfortunately, osimertinib monotherapy inevitably leads to both EGFR-dependent and EGFR-independent resistance mechanisms that reactivate RTK/MAPK pathway signaling. Thus, exploration of new combination strategies that target RTK/MAPK-mediated bypass of EGFR dependence may circumvent or delay therapeutic resistance are a key research focus. Preclinically, it has been shown that EGFR-mutant NSCLC cell lines are sensitive to inhibition of an upstream node of the MAPK pathway, the Son of Sevenless homolog 1 (SOS1) protein, which functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases. MRTX0902 is a selective and potent SOS1 inhibitor currently in Phase 1 clinical trials and functions by disrupting the KRAS/SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS, ultimately leading to downregulation of KRAS-MAPK pathway signaling. Here we demonstrate that dual inhibition of SOS1 and mutant EGFR by osimertinib results in greater anchorage-independent (3D) cell death and further downregulation of MAPK and PI3K/AKT pathway signaling compared to single agent osimertinib treatment. In our current study, we characterized the anti-tumor effects of SOS1 inhibition by MRTX0902 as a monotherapy and in combination with osimertinib in EGFR mutant models of NSCLC. While single agent MRTX0902 treatment effectively inhibited EGFR mutant cell survival, combination treatment of MRTX0902 with osimertinib resulted in (1) deeper and sustained inhibition of MAPK and PI3K/AKT pathway signaling, (2) enhanced inhibition of 3D cell viability and increased apoptosis, and (3) increased anti-tumor efficacy compared to osimertinib monotherapy in EGFR mutant CDX models in vivo. These studies uncover the potential clinical application of combined vertical inhibition of RTK/MAPK pathway signaling by osimertinib and MRTX0902 and ultimately aide in the understanding of EGFR and RAS biology in targeted cancer therapy. Citation Format: Shilpi Khare, Niranjan Sudhakar, Jade Laguer, David M. Briere, Larry Yan, Allan Hebbert, Andrew Calinisan, Lars D. Engstrom, Fadia Qiryaqos, Peter Olson, James G. Christensen, Jacob R. Haling. Inhibition of SOS1 by MRTX0902 augments the anti-tumor response of the targeted EGFR inhibitor osimertinib in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3499.
KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the MAPK pathway. Recent data has consistently demonstrated co-dependencies of mutant-KRAS with extrinsic proteins that augment GTP-loading. Son of Sevenless homolog 1 (SOS1) is the most proximal of these proteins to KRAS and functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases, thus representing a highly sought-after druggable target. Utilizing a structure-based drug discovery approach, we identified a selective and potent SOS1 inhibitor, MRTX0902, that functions by disrupting the KRAS/SOS1 protein-protein interaction, ultimately preventing SOS1-mediated nucleotide exchange on KRAS. MRTX0902 enhances the anti-tumor activity of the KRASG12C inhibitor adagrasib across multiple KRASG12C-mutant preclinical models; however, it is anticipated that deeper pharmacological inhibition of KRAS signaling may give rise to novel combination targets and additional adaptive resistance mechanisms. To identify additional vulnerabilities and combination strategies, we conducted drug-anchored CRISPR screens in two KRASG12C xenograft models in the presence of MRTX0902 and adagrasib in vitro and in vivo. Interestingly, we found that the SOS1 homolog, SOS2, only emerges as a co-dependency under selective pressure of combination treatment and likely compensates for the inhibition of SOS1. Furthermore, multiple components from the PIK3CA/mTOR signaling pathway, PRMT5, and other non-vertical signal transduction pathways were uncovered and identified as genetic co-dependencies that emerged under selective pressure. Conversely, tumor suppressor genes including TSC1/2, PTEN, NF1, KEAP1 and TP53 along with phosphatases PTPN12 and PTPN14 enhanced tumor growth when knocked out providing a catalogue of putative resistance genes and mechanisms. Lastly, we utilized small molecule inhibitors of putative therapeutic targets identified from our CRISPR screens to validate genetic co-dependencies across in vitro and in vivo translational models. These studies uncover the potential utility of additional drug partners for the MRTX0902 and adagrasib combination and aide in the understanding of SOS and RAS biology in targeted cancer therapy. Citation Format: Shilpi Khare, Niranjan Sudhakar, David M. Briere, Larry Yan, Lars D. Engstrom, Jade Laguer, James Medwid, Laura Vegar, Darin Vanderpool, Matthew A. Marx, John M. Ketcham, James G. Christensen, Peter Olson, Jacob R. Haling. Chemical genomics identify novel druggable nodes and resistance pathways in the presence of concomitant SOS1 and KRAS inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB193.
KRAS mutations are the most common activating mutations in human cancer that ultimately lead to hyperactivation of the MAPK pathway and uncontrolled growth. KRAS functions as a small GTPase that cycles through its GTP-loaded “on” state and its GDP-loaded “off” state, a highly regulated process that is crucial for normal cell proliferation and survival. The guanine nucleotide exchange factor (GEF) SOS1 plays a critical role in this process by regulating the “on/off” state of KRAS. The protein-protein interaction between SOS1 and KRAS facilitates turnover of KRAS from the GDP-loaded inactive state to its activated and GTP-loaded state, a critical step to enable productive KRAS effector binding and activation of downstream signaling. The KRASG12C inhibitor, adagrasib (MRTX849), irreversibly binds to the GDP-loaded inactive conformation of KRASG12C and has recently shown encouraging clinical activity across several cancer types. As adagrasib binds preferentially to the inactive state of KRAS, blockade of SOS1 is anticipated to shift KRASG12C into the adagrasib-susceptible GDP-loaded state. Furthermore, this combination strategy could be used to target other mutant-driven cancers within the MAPK pathway using the appropriate KRASmut inhibitors and/or inhibitors of other targets within the MAPK pathway including MEK or EGFR. MRTX0902 was identified using iterative structure-based design as a selective inhibitor of SOS1 that demonstrates an IC50 value of 2 nM in a SOS1 HTRF binding assay and 30 nM in an MKN1 cellular assay. In pharmacokinetic evaluation across species, MRTX0902 demonstrated low extraction ratios and moderate to high bioavailability in mice, rats, and dogs. In preclinical models, MRTX0902 augmented the antitumor activity of adagrasib and other selected therapies. The design, discovery, and preclinical characterization of the potential best-in-class candidate MRTX0902 will be described. Citation Format: John M. Ketcham, David M. Briere, Aaron C. Burns, James G. Christensen, Robin J. Gunn, Jacob Haling, Anthony Ivetac, Shilpi Khare, Jon Kuehler, Svitlana Kulyk, Jade Laguer, John D. Lawson, Krystal Moya, Natalie Nguyen, Peter Olson, Lisa Rahbaek, Christopher R. Smith, Niranjan Sudhakar, Nicole C. Thomas, Darin Vanderpool, Xiaolun Wang, Matthew A. Marx. Design and discovery of MRTX0902, a potent, selective, and orally bioavailable SOS1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB505.
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