No abstract

Colorectal cancer (CRC) remains an unmet medical need where more than 50% off patients have tumors that are driven by somatic mutations in the RAS/MAPK signaling pathway. Targeted therapies, such as anti-EGFR inhibitors for patients with BRAFwt/RASwt CRC tumors and encorafenib + cetuximab for patients with BRAFV600E CRC tumors, are available treatment options but demonstrate both limited overall response rates and duration of response (Yaeger, 2018). In particular, in the previously treated setting, overall survival is typically less than a year (Grothey, 2013; Mayer, 2015; Kopetz, 2019). In addition, targeted treatment options are limited for patients harboring KRAS or NRAS mutations as emergence of these mutations is a predictive biomarker to anti-EGFR therapy resistance in metastatic CRC. ERAS-007 is a selective ERK1/2 inhibitor targeting the terminal node of the RAS/MAPK signaling pathway. In addition, ERAS-007 demonstrates single digit nanomolar biochemical ERK1/2 inhibition as well as a durable target residence time, thus making it a promising combination partner in RAS/MAPK pathway activated or altered CRC. To this end, ERAS-007 was evaluated in preclinical models in combination with encorafenib + cetuximab in BRAFV600E CRC and with palbociclib in KRASmut CRC. ERAS-007 demonstrated monotherapy activity and combination benefit in cell-based assays as well as superior combination efficacy in vivo relative to respective monotherapy control arms. In summary, ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models both as a monotherapy and in combination that support further exploration in the clinic. Accordingly, ERAS-007 combinations with encorafenib + cetuximab in BRAFV600E CRC and with palbociclib in KRASmut CRC are currently being evaluated in the HERKULES-3 phase 1b/2 master protocol (NCT05039177). Citation Format: Erin D. Lew, Joanne Oh, Taylor Congdon, Jingchuan Zhang, Robert F. Shoemaker. ERAS-007 is a selective ERK1/2 inhibitor with preclinical activity across RAS/MAPK pathway-driven CRC models [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 2672.

The RAS family of GTPases, which include KRAS, NRAS, and HRAS, are key regulators of cellular signaling, acting as molecular switches downstream of receptor tyrosine kinases (RTKs) and as key regulators of the RAS/MAPK pathway. RAS cycles between inactive (GDP) and active (GTP) states to regulate the activity of the RAS/MAPK pathway. In many cancers, activating KRAS mutations enable KRAS to persist in the active GTP-bound state, resulting in hyperactive RAS/MAPK pathway signaling that drives cell growth and survival. The KRAS G12C mutation occurs in 14% of lung adenocarcinoma, a cancer type that frequently metastasizes to the brain (40%). To address the high prevalence of KRAS G12C mutant CNS metastases in lung adenocarcinoma, we are developing CNS-penetrant covalent KRAS G12C inhibitors (“ERAS G12Ci’s”) to treat both CNS and systemic disease. ERAS G12Ci’s rapidly form covalent adducts with the KRAS G12C protein in its inactive GDP state and exhibit low nanomolar IC50’s in a nucleotide exchange assay. ERAS G12Ci’s demonstrate high selectivity in a cell-based proteome selectivity assay and inhibit the growth of RAS Initiative KRAS G12C mutant cells, and not RAS Initiative KRAS WT cells. ERAS G12Ci’s potently inhibit cell proliferation in 3-dimensional Cell-Titer Glo (3D-CTG) assays in KRAS G12C mutant lung and pancreatic cell lines (NCI-H1373, NCI-H2122, and MIA PaCa-2). Mechanistically, ERAS G12Ci’s blocked RAS-RAF complex formation and inhibited ERK1/2 phosphorylation. This in vitro activity translates in vivo where ERAS G12Ci’s induce pharmacodynamic modulation in the pancreatic cancer MIA PaCa-2 model. ERAS G12Ci’s significantly inhibit tumor growth in NCI-H1373 and NCI-H2122 CDX lung adenocarcinoma and MIA PaCa-2 PDAC models. No meaningful body weight loss or clinical adverse events were observed with any of these compounds. Human efflux transporter substrate assessments indicate that ERAS G12Ci’s are either not substrates or weak/modest substrates of P-gp, a crucial efflux transporter that can limit CNS penetration. In rat CNS studies, these inhibitors exhibit good CNS penetration performance as measured by brain-to-plasma partition coefficients, which are comparable to those of approved CNS-active small molecule inhibitors. Daily oral administration demonstrates dose-dependent tumor regression in intracranial and intra-carotid injection (ICA) KRAS G12C CDX models. We are optimizing multiple covalent CNS-penetrant KRAS G12C inhibitors that exhibit both CNS and systemic activity in vivo. Citation Format: Jae Hyun Bae, Erin D. Lew, Jun Feng, Marcos Gonzalez-Lopez, Joanne Oh, Patrick Fagan, Matt Salie, Nick Isley, Richard Lam, Adriana Irimia, Robin Nevarez, Bingzhen Lin, Taylor Congdon, Jingchuan Zhang, Dawei Xuan, Ping Chen, Jean-Michel Vernier, Robert Shoemaker. Discovery of potent CNS-penetrant covalent KRAS G12C inhibitors [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 2675.

KRAS mutations occur in about 25% of all cancers and promote oncogenesis via constitutive activation of the RAS/MAPK pathway. Targeting KRAS mutant tumors by inhibiting individual nodes in the RAS/MAPK pathway, including SHP2, SOS1, KRAS, RAF, MEK, and ERK, has shown early clinical activity, but the rapid emergence of resistance limits the benefit of monotherapy. Resistance is often mediated by reactivation of RAS/MAPK pathway signaling, which can occur by increased activation of upstream of the RAS/MAPK pathway (e.g., EGFR activation) and/or activation of RAS/MAPK pathway nodes (e.g., oncogenic BRAF and MEK mutations). Inhibiting both upstream and downstream RAS/MAPK pathway nodes has the potential to more robustly prevent reactivation relative to inhibition of a single node alone. We are currently exploring the combination of an inhibitor of an upstream node, SHP2, with ERAS-601 and the terminal downstream node, ERK1/2, with ERAS-007 (our first “MAPKlamp”) in nonclinical models. We evaluated this MAPKlamp in NSCLC, CRC, and pancreatic tumor models that harbored KRAS mutations in vitro and in vivo. In 14-day clonogenic assays in KRAS mutant NSCLC, CRC, and PDAC cell lines, this MAPKlamp inhibited colony growth more potently than ERAS-601 or ERAS-007 alone. In KRAS mutant CDX and PDX models, this MAPKlamp’s in vitro activity was observed in vivo where it achieved superior tumor growth inhibition and tumor regression relative to ERAS-601 and ERAS-007 monotherapy. This MAPKlamp showed in vitro and in vivo combination activity in KRAS mutant tumors, and these results support its clinical evaluation in RAS/MAPK pathway-driven tumors. Citation Format: Leenus Martin, Erin D. Lew, Roopal Patel, Joanne Oh, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Wei Lin, Les Brail, Robert Shoemaker. ERAS-007 (ERK inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models [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 2669.