bims-pimaco 2024-03-31 papers

bims-pimaco

Biomed News

on PI3K and MAPK signalling in colorectal cancer

Issue of 2024–03–31
six papers selected by
Lucas B. Zeiger

Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver.
Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer.
Upregulation of ATF4 mediates the cellular adaptation to pharmacologic inhibition of amino acid transporter LAT1 in pancreatic ductal adenocarcinoma cells.
Non-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP2-mediated endocytosis.
Paradoxical activation of oncogenic signaling as a cancer treatment strategy.
Embracing cancer complexity: Hallmarks of systemic disease.

Int J Mol Sci. 2024 Mar 14. pii: 3304. [Epub ahead of print]25(6):

Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver.

Javier Ros, Caterina Vaghi, Iosune Baraibar, Nadia Saoudi González, Marta Rodríguez-Castells, Ariadna García, Adriana Alcaraz, Francesc Salva, Josep Tabernero, Elena Elez.

  Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

Keywords:  KRAS G12C colorectal cancer; KRAS inhibitor; liquid biopsy; mechanism of resistance; pocket

DOI:  https://doi.org/10.3390/ijms25063304
Lancet Oncol. 2024 Apr;pii: S1470-2045(23)00676-9. [Epub ahead of print]25(4): e139-e151

Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer.

Iseult M Browne, Fabrice André, Sarat Chandarlapaty, Lisa A Carey, Nicholas C Turner.

The growing availability of targeted therapies for patients with advanced oestrogen receptor-positive breast cancer has improved survival, but there remains much to learn about the optimal management of these patients. The PI3K-AKT and mTOR pathways are among the most commonly activated pathways in breast cancer, whose crucial role in the pathogenesis of this tumour type has spurred major efforts to target this pathway at specific kinase hubs. Approvals for oestrogen receptor-positive advanced breast cancer include the PI3K inhibitor alpelisib for PIK3CA-mutated tumours, the AKT inhibitor capivasertib for tumours with alterations in PIK3CA, AKT1, or PTEN, and the mTOR inhibitor everolimus, which is used irrespective of mutation status. The availability of different inhibitors leaves physicians with a potentially challenging decision over which of these therapies should be used for individual patients and when. In this Review, we present a comprehensive summary of our current understanding of the pathways and the three inhibitors and discuss strategies for the optimal sequencing of therapies in the clinic, particularly after progression on a CDK4/6 inhibitor.

DOI: https://doi.org/10.1016/S1470-2045(23)00676-9
J Pharmacol Sci. 2024 May;pii: S1347-8613(24)00027-6. [Epub ahead of print]155(1): 14-20

Upregulation of ATF4 mediates the cellular adaptation to pharmacologic inhibition of amino acid transporter LAT1 in pancreatic ductal adenocarcinoma cells.

Yu Ma, Suguru Okuda, Hiroki Okanishi, Minhui Xu, Chunhuan Jin, Hitoshi Endou, Ryuichi Ohgaki, Yoshikatsu Kanai.

  L-type amino acid transporter 1 (LAT1) is recognized as a promising target for cancer therapy; however, the cellular adaptive response to its pharmacological inhibition remains largely unexplored. This study examined the adaptive response to LAT1 inhibition using nanvuranlat, a high-affinity LAT1 inhibitor. Proteomic analysis revealed the activation of a stress-induced transcription factor ATF4 following LAT1 inhibition, aligning with the known cellular responses to amino acid deprivation. This activation was linked to the GCN2-eIF2α pathway which regulates translation initiation. Our results show that ATF4 upregulation counteracts the suppressive effect of nanvuranlat on cell proliferation in pancreatic ductal adenocarcinoma cell lines, suggesting a role for ATF4 in cellular adaptation to LAT1 inhibition. Importantly, dual targeting of LAT1 and ATF4 exhibited more substantial anti-proliferative effects in vitro than individual treatments. This study underscores the potential of combining LAT1 and ATF4 inhibition as a therapeutic strategy in cancer treatment.

Keywords:  ATF4; Amino acid transporter; LAT1; Nanvuranlat; Pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.jphs.2024.03.001
Nat Commun. 2024 Mar 23. 15(1): 2612

Non-catalytic role of phosphoinositide 3-kinase in mesenchymal cell migration through non-canonical induction of p85β/AP2-mediated endocytosis.

Hideaki T Matsubayashi, Jack Mountain, Nozomi Takahashi, Abhijit Deb Roy, Tony Yao, Amy F Peterson, Cristian Saez Gonzalez, Ibuki Kawamata, Takanari Inoue.

Class IA phosphoinositide 3-kinase (PI3K) galvanizes fundamental cellular processes such as migration, proliferation, and differentiation. To enable these multifaceted roles, the catalytic subunit p110 utilizes the multi-domain, regulatory subunit p85 through its inter SH2 domain (iSH2). In cell migration, its product PI(3,4,5)P3 generates locomotive activity. While non-catalytic roles are also implicated, underlying mechanisms and their relationship to PI(3,4,5)P3 signaling remain elusive. Here, we report that a disordered region of iSH2 contains AP2 binding motifs which can trigger clathrin and dynamin-mediated endocytosis independent of PI3K catalytic activity. The AP2 binding motif mutants of p85 aberrantly accumulate at focal adhesions and increase both velocity and persistency in fibroblast migration. We thus propose the dual functionality of PI3K in the control of cell motility, catalytic and non-catalytic, arising distinctly from juxtaposed regions within iSH2.

DOI: https://doi.org/10.1038/s41467-024-46855-y
Cancer Discov. 2024 Mar 27.

Paradoxical activation of oncogenic signaling as a cancer treatment strategy.

Matheus Henrique Dias, Anoek Friskes, Siying Wang, Joao M Fernandes Neto, Frank van Gemert, Soufiane Mourragui, Chrysa Papagianni, Hendrik J Kuiken, Sara Mainardi, Daniel Alvarez-Villanueva, Cor Lieftink, Ben Morris, Anna Dekker, Emma van Dijk, Lieke H S Wilms, Marcelo S da Silva, Robin A Jansen, Antonio Mulero-Sanchez, Elke Malzer, August Vidal, Cristina Santos, Ramon Salazar, Rosangela A M Wailemann, Thompson E P Torres, Giulia De Conti, Jonne A Raaijmakers, Petur Snaebjornsson, Shengxian Yuan, Wenxin Qin, John S Kovach, Hugo A Armelin, Hein Te Riele, Alexander van Oudernaarden, Haojie Jin, Roderick L Beijersbergen, Alberto Villanueva, Rene H Medema, Rene Bernards.

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of Protein Phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0216
Cell. 2024 Mar 28. pii: S0092-8674(24)00175-2. [Epub ahead of print]187(7): 1589-1616

Embracing cancer complexity: Hallmarks of systemic disease.

Charles Swanton, Elsa Bernard, Chris Abbosh, Fabrice André, Johan Auwerx, Allan Balmain, Dafna Bar-Sagi, René Bernards, Susan Bullman, James DeGregori, Catherine Elliott, Ayelet Erez, Gerard Evan, Mark A Febbraio, Andrés Hidalgo, Mariam Jamal-Hanjani, Johanna A Joyce, Matthew Kaiser, Katja Lamia, Jason W Locasale, Sherene Loi, Ilaria Malanchi, Miriam Merad, Kathryn Musgrave, Ketan J Patel, Sergio Quezada, Jennifer A Wargo, Ashani Weeraratna, Eileen White, Frank Winkler, John N Wood, Karen H Vousden, Douglas Hanahan.

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.

DOI: https://doi.org/10.1016/j.cell.2024.02.009