Ruiping Zhao

Abstract Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations 1,2 . RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants 3 . More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS 4 . Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Coronary heart disease (CHD) is one of the leading causes of death worldwide. CHD is characterized by formation of arterial plaques which are mainly comprised of lipids, calcium and inflammatory cells. These plaques narrow the lumen of coronary arteries leading to episodic or persistent angina. Rupture of these plaques leads to the formation of thrombus, which as a result of cessation of blood flow, causes myocardial infarct and death. CHD is exacerbated by risk factors including obesity, diabetes mellitus, and hypertension. Diagnosis is established by the level of blood cholesterol, triglycerides and lipoproteins Inflammation is considered significant in the pathogenesis of CHD and for this reason, severity and prognosis of CHD is assessed by the levels of inflammatory biomarkers, including interleukin-6, C-reactive protein (CRP), complement, CD40 and myeloperoxidase (MPO).

Coronary heart disease (CHD) is one of the leading causes of death worldwide. CHD is characterized by formation of arterial plaques which are mainly comprised of lipids, calcium and inflammatory cells. These plaques narrow the lumen of coronary arteries leading to episodic or persistent angina. Rupture of these plaques leads to the formation of thrombus, which as a result of cessation of blood flow, causes myocardial infarct and death. CHD is exacerbated by risk factors including obesity, diabetes mellitus, and hypertension. Diagnosis is established by the level of blood cholesterol, triglycerides and lipoproteins Inflammation is considered significant in the pathogenesis of CHD and for this reason, severity and prognosis of CHD is assessed by the levels of inflammatory biomarkers, including interleukin-6, C-reactive protein (CRP), complement, CD40 and myeloperoxidase (MPO).

Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.

Abstract KRASG12D is the most frequent KRAS mutation in human cancers, with the highest prevalence in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). RMC-9805 is a first-in-class, oral, mutant-selective covalent inhibitor of the GTP-bound and active RAS(ON) form of KRASG12D. The formation of a stable, high affinity tri-complex between RMC-9805, KRASG12D and cyclophilin A results in the suppression of signaling downstream of KRASG12D(ON) by disrupting its interactions with downstream effectors such as RAF kinases. RMC-9805 treatment caused selective and persistent modification of KRASG12D leading to deep and durable suppression of RAS pathway activity, inhibition of cell proliferation, and apoptosis induction in KRASG12D human cancer cell lines in vitro and tumor models in vivo. In a mouse clinical trial with KRASG12D xenograft tumor models, RMC-9805 administered orally as a single agent was well tolerated and induced objective responses in 7 of 9 PDAC PDX and CDX models and 6 of 9 NSCLC PDX models, as assessed by mRECIST. In the few models that exhibited sub-optimal responses to RMC-9805 monotherapy, combination treatment with various RAS Companion Inhibitors improved depth and/or duration of anti-tumor response. In contrast to RASMUTANT NSCLC and PDAC, CRC tumors are less dependent on RAS driver mutations. For example, a more heterogeneous response to KRASG12C inhibitors has been reported in CRC than in NSCLC patients, suggesting combinations will be desired to achieve significant clinical benefit in CRC. Likewise, RMC-9805 monotherapy is less active in CRC models at doses that were highly active in KRASG12D NSCLC and PDAC models. However, combinations of RMC-9805 with vertical or parallel pathway RAS Companion Inhibitors such as SHP2, mTORC1 or RASMULTI(ON) inhibitors, achieved objective response rates up to 60% and delayed the onset of resistance in tumor models in vivo. RMC-9805 also synergized with anti-PD1 therapy in KRASG12D tumors in immune-competent animal models by shaping a favorable tumor immune microenvironment through cytokine modulation. In addition, RMC-9805 engaged the adaptive immune system by increasing presentation and recognition of tumor antigens, promoting a diversification of the TCR repertoire, and inducing immunological memory. Overall, RMC-9805 monotherapy elicited tumor regressions in most preclinical PDAC and NSCLC cancer models harboring KRASG12D. Furthermore, RMC-9805 combination therapies drove regressions in CRC models relatively less responsive to monotherapy. Supported by these findings, RMC-9805 is currently in IND-enabling development to permit clinical evaluation of single agent and combination strategies in patients with KRASG12D tumors. Citation Format: Lingyan Jiang, Marie Menard, Caroline Weller, Zhican Wang, Les Burnett, Ida Aronchik, Shelby Steele, Mike Flagella, Ruiping Zhao, James W W. Evans, Shook Chin, Kang-Jye Chou, Yunming Mu, Michael Longhi, Laura McDowell, John E. Knox, Adrian Gill, Jacqueline A. Smith, Mallika Singh, Elsa Quintana, Jingjing Jiang. RMC-9805, a first-in-class, mutant-selective, covalent and oral KRASG12D(ON) inhibitor that induces apoptosis and drives tumor regression in preclinical models of KRASG12D cancers [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 526.