bims-pimaco 2024-04-14 papers

bims-pimaco

Biomed News

on PI3K and MAPK signalling in colorectal cancer

Issue of 2024–04–14
eight papers selected by
Lucas B. Zeiger

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.
Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.
Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.
Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer.
Differential landscape of immune evasion in oncogenic RAS-driven primary and metastatic colorectal cancers.
The epigenetic landscape in intestinal stem cells and its deregulation in colorectal cancer.
The pan-RAF-MEK non degrading molecular glue NST-628 is a potent and brain penetrant inhibitor of the RAS-MAPK pathway with activity across diverse RAS- and RAF-driven cancers.
Comprehensive Characterization of LAT1 Cholesterol-Binding Sites.

Nature. 2024 Apr 08.

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

Matthew Holderfield, Bianca J Lee, Jingjing Jiang, Aidan Tomlinson, Kyle J Seamon, Alessia Mira, Enrico Patrucco, Grace Goodhart, Julien Dilly, Yevgeniy Gindin, Nuntana Dinglasan, Yingyun Wang, Lick Pui Lai, Shurui Cai, Lingyan Jiang, Nicole Nasholm, Nataliya Shifrin, Cristina Blaj, Harshit Shah, James W Evans, Nilufar Montazer, Oliver Lai, Jade Shi, Ethan Ahler, Elsa Quintana, Stephanie Chang, Anthony Salvador, Abby Marquez, Jim Cregg, Yang Liu, Anthony Milin, Anqi Chen, Tamar Bar Ziv, Dylan Parsons, John E Knox, Jennifer E Klomp, Jennifer Roth, Matthew Rees, Melissa Ronan, Antonio Cuevas-Navarro, Feng Hu, Piro Lito, David Santamaria, Andrew J Aguirre, Andrew M Waters, Channing J Der, Chiara Ambrogio, Zhengping Wang, Adrian L Gill, Elena S Koltun, Jacqueline A M Smith, David Wildes, Mallika Singh.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

DOI: https://doi.org/10.1038/s41586-024-07205-6
Cancer Discov. 2024 Apr 09. OF1-OF24

Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.

Jingjing Jiang, Lingyan Jiang, Benjamin J Maldonato, Yingyun Wang, Matthew Holderfield, Ida Aronchik, Ian P Winters, Zeena Salman, Cristina Blaj, Marie Menard, Jens Brodbeck, Zhe Chen, Xing Wei, Michael J Rosen, Yevgeniy Gindin, Bianca J Lee, James W Evans, Stephanie Chang, Zhican Wang, Kyle J Seamon, Dylan Parsons, James Cregg, Abby Marquez, Aidan C A Tomlinson, Jason K Yano, John E Knox, Elsa Quintana, Andrew J Aguirre, Kathryn C Arbour, Abby Reed, W Clay Gustafson, Adrian L Gill, Elena S Koltun, David Wildes, Jacqueline A M Smith, Zhengping Wang, Mallika Singh.

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985).
SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0027
Cancer Discov. 2024 Apr 08. OF1-OF12

Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer.

Rona Yaeger, Nataliya V Uboha, Meredith S Pelster, Tanios S Bekaii-Saab, Minal Barve, Joel Saltzman, Joshua K Sabari, Julio A Peguero, Andrew Scott Paulson, Pasi A Jänne, Marcia Cruz-Correa, Kenna Anderes, Karen Velastegui, Xiaohong Yan, Hirak Der-Torossian, Samuel J Klempner, Scott E Kopetz.

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2-7.6). Median progression-free survival was 6.9 months (95% CI, 5.7-7.4) and median overall survival was 15.9 months (95% CI, 11.8-18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3-4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance.
SIGNIFICANCE: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0217
Nature. 2024 Apr 08.

Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer.

Urszula N Wasko, Jingjing Jiang, Tanner C Dalton, Alvaro Curiel-Garcia, A Cole Edwards, Yingyun Wang, Bianca Lee, Margo Orlen, Sha Tian, Clint A Stalnecker, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Stephen A Sastra, Carmine F Palermo, Marie C Hasselluhn, Amanda R Decker-Farrell, Stephanie Chang, Lingyan Jiang, Xing Wei, Yu C Yang, Ciara Helland, Haley Courtney, Yevgeniy Gindin, Karl Muonio, Ruiping Zhao, Samantha B Kemp, Cynthia Clendenin, Rina Sor, William P Vostrejs, Priya S Hibshman, Amber M Amparo, Connor Hennessey, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Jens Brodbeck, Lorenzo Tomassoni, Basil Bakir, Nicholas D Socci, Laura E Herring, Natalie K Barker, Junning Wang, James M Cleary, Brian M Wolpin, John A Chabot, Michael D Kluger, Gulam A Manji, Kenneth Y Tsai, Miroslav Sekulic, Stephen M Lagana, Andrea Califano, Elsa Quintana, Zhengping Wang, Jacqueline A M Smith, Matthew Holderfield, David Wildes, Scott W Lowe, Michael A Badgley, Andrew J Aguirre, Robert H Vonderheide, Ben Z Stanger, Timour Baslan, Channing J Der, Mallika Singh, Kenneth P Olive.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations1,2. 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 (WT) variants (RAS(ON) multi-selective)3. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS4, we assessed the therapeutic potential of the RAS(ON) multi-selective inhibitor RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumor activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors 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 model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumors 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.

DOI: https://doi.org/10.1038/s41586-024-07379-z
Mol Ther Oncol. 2024 Mar 21. 32(1): 200786

Differential landscape of immune evasion in oncogenic RAS-driven primary and metastatic colorectal cancers.

Emil Lou, Joanne Xiu, Yasmine Baca, Anwaar Saeed, Ajay Prakash, Sepideh Gholami, Subbaya Subramanian, Timothy K Starr, Elisa Fontana, Ritu Pandey, Heinz-Josef Lenz, Anthony F Shields, Chadi Nabhan, Matthew Oberley, Andreas Seeber, Wafik El-Deiry.

  Oncogenic drivers such as KRAS extensively modulate the tumor inflammatory microenvironment (TIME) of colorectal cancer (CRC). The influence of KRAS on modulating immune cell composition remains unclear. The objective of this study was to identify signatures of infiltrative immune cells and distinctive patterns that differ between RAS wild-type (WT) and oncogenic mutant (MT) CRC that explain immune evasion in MT tumors. A total of 7,801 CRC specimens were analyzed using next-generation DNA sequencing, whole-exome sequencing, and/or whole transcriptome sequencing. Deficiency of mismatch repair (dMMR)/microsatellite instability (MSI) and tumor mutation burden (TMB) were also assessed. KRAS mutations were present in 48% of CRC, similarly distributed in patients younger than vs. 50 years and older. In microsatellite stable (MSS) KRAS MT tumors, composition of the TIME included higher neutrophil infiltration and lower infiltration of B cells. MSI-H/dMMR was significantly more prevalent in RAS WT (9.1%) than in KRAS MT (2.9%) CRC. In MSS CRC, TMB-high cases were significantly higher in RAS MT (3.1%) than in RAS WT (2.1%) tumors. KRAS and NRAS mutations are associated with increased neutrophil infiltration, with codon-specific differences. These results demonstrate significant differences in the TIME of RAS mutant CRC that match previous reports of immunoevasive characteristics of such tumors.

Keywords:  KRAS; MT: Regular Issue; RAS; colorectal cancer; early-onset colorectal cancer; immune infiltration; immunoevasion; next-generation sequencing; tumor immune microenvironment; tumor microenvironment; young-adult colorectal cancer

DOI:  https://doi.org/10.1016/j.omton.2024.200786
Stem Cells. 2024 Apr 10. pii: sxae027. [Epub ahead of print]

The epigenetic landscape in intestinal stem cells and its deregulation in colorectal cancer.

Axelle Larue, Yaser Atlasi.

  Epigenetic mechanisms play a pivotal role in controlling gene expression and cellular plasticity in both normal physiology and pathophysiological conditions. These mechanisms are particularly important in the regulation of stem cell self-renewal and differentiation, both in embryonic development and within adult tissues. A prime example of this finely tuned epigenetic control is observed in the gastrointestinal lining, where the small intestine undergoes renewal approximately every 3-5 days. How various epigenetic mechanisms modulate chromatin functions in intestinal stem cells (ISCs) is currently an active area of research. In this review, we discuss the main epigenetic mechanisms that control ISC differentiation under normal homeostasis. Furthermore, we explore the dysregulation of these mechanisms in the context of colorectal cancer (CRC) development. By outlining the main epigenetic mechanisms contributing to CRC, we highlight the recent therapeutics development and future directions for colorectal cancer research.

Keywords:  Chromatin; Colorectal Cancer; Epigenetics; Intestinal Stem Cells

DOI:  https://doi.org/10.1093/stmcls/sxae027
Cancer Discov. 2024 Apr 08.

The pan-RAF-MEK non degrading molecular glue NST-628 is a potent and brain penetrant inhibitor of the RAS-MAPK pathway with activity across diverse RAS- and RAF-driven cancers.

Meagan B Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E Cohen, Brooke M Swalm, Chun Li, Aysegul Ozen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C Dar, Yongxin Han, Klaus P Hoeflich, Michael Hale, Margit Hagel.

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0139
J Chem Theory Comput. 2024 Apr 10.

Comprehensive Characterization of LAT1 Cholesterol-Binding Sites.

Keino Hutchinson, Avner Schlessinger.

The human L-type amino acid transporter 1 (LAT1; SLC7A5), is an amino acid exchanger protein, primarily found in the blood-brain barrier, placenta, and testis, where it plays a key role in amino acid homeostasis. Cholesterol is an essential lipid that has been highlighted to play a role in regulating the activity of membrane transporters, such as LAT1, yet little is known about the molecular mechanisms driving this phenomenon. Here we perform a comprehensive computational analysis to investigate cholesterol's role in LAT1 structure and function, focusing on four cholesterol-binding sites (CHOL1-4) identified in a recent LAT1-apo inward-open conformation cryo-EM structure. Through a series of independent molecular dynamics (MD) simulations, molecular docking, MM/GBSA free energy calculations, and other analysis tools, we explored the interactions between LAT1 and cholesterol. Our findings suggest that CHOL3 forms the most stable and favorable interactions with LAT1. Principal component analysis (PCA) and center of mass (COM) distance assessments show that CHOL3 binding stabilizes the inward-open state of LAT1 by preserving the spatial arrangement of the hash and bundle domains. Additionally, we propose an alternative cholesterol-binding site for originally assigned CHOL1. Overall, this study improves the understanding of cholesterol's modulatory effect on LAT1 and proposes candidate sites for the discovery of future allosteric ligands with rational design.

DOI: https://doi.org/10.1021/acs.jctc.3c01391