bims-pimaco 2024-04-28 papers

Curr Oncol. 2024 Apr 03. 31(4): 2024-2046

KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance.

Leonard J Ash, Ottavia Busia-Bourdain, Daniel Okpattah, Avrosina Kamel, Ariel Liberchuk, Andrew L Wolfe.

KRAS is a small GTPase that is among the most commonly mutated oncogenes in cancer. Here, we discuss KRAS biology, therapeutic avenues to target it, and mechanisms of resistance that tumors employ in response to KRAS inhibition. Several strategies are under investigation for inhibiting oncogenic KRAS, including small molecule compounds targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory strategies. A central challenge to therapeutic effectiveness is the frequent development of resistance to these treatments. Direct resistance mechanisms can involve KRAS mutations that reduce drug efficacy or copy number alterations that increase the expression of mutant KRAS. Indirect resistance mechanisms arise from mutations that can rescue mutant KRAS-dependent cells either by reactivating the same signaling or via alternative pathways. Further, non-mutational forms of resistance can take the form of epigenetic marks, transcriptional reprogramming, or alterations within the tumor microenvironment. As the possible strategies to inhibit KRAS expand, understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations.

Keywords: KRAS; cancer; immunotherapy; inhibitors; mutation; oncogene; resistance; targeted therapy

DOI: https://doi.org/10.3390/curroncol31040150

Oncogene. 2024 Apr 23.

Identification of genes that promote PI3K pathway activation and prostate tumour formation.

Jeffrey C Francis, Amy Capper, Alistair G Rust, Klea Ferro, Jian Ning, Wei Yuan, Johann de Bono, Stephen J Pettitt, Amanda Swain.

We have performed a functional in vivo mutagenesis screen to identify genes that, when altered, cooperate with a heterozygous Pten mutation to promote prostate tumour formation. Two genes, Bzw2 and Eif5a2, which have been implicated in the process of protein translation, were selected for further validation. Using prostate organoid models, we show that either Bzw2 downregulation or EIF5A2 overexpression leads to increased organoid size and in vivo prostate growth. We show that both genes impact the PI3K pathway and drive a sustained increase in phospho-AKT expression, with PTEN protein levels reduced in both models. Mechanistic studies reveal that EIF5A2 is directly implicated in PTEN protein translation. Analysis of patient datasets identified EIF5A2 amplifications in many types of human cancer, including the prostate. Human prostate cancer samples in two independent cohorts showed a correlation between increased levels of EIF5A2 and upregulation of a PI3K pathway gene signature. Consistent with this, organoids with high levels of EIF5A2 were sensitive to AKT inhibitors. Our study identified novel genes that promote prostate cancer formation through upregulation of the PI3K pathway, predicting a strategy to treat patients with genetic aberrations in these genes particularly relevant for EIF5A2 amplified tumours.

DOI: https://doi.org/10.1038/s41388-024-03028-x

Cancer Lett. 2024 Apr 18. pii: S0304-3835(24)00297-0. [Epub ahead of print] 216904

Site-Specific Mutagenesis Screening in KRASG12D Mutant Library to Uncover Resistance Mechanisms to KRASG12D Inhibitors.

Jeesoo Choi, Ju-Young Shin, Taeyul K Kim, Kiwook Kim, Jiyun Kim, Eunhye Jeon, Juyeong Park, Yoon Dae Han, Kyung-A Kim, Taebo Sim, Hui Kwon Kim, Han Sang Kim.

KRAS plays a crucial role in regulating cell survival and proliferation and is one of the most commonly mutated oncogenes in human cancers. The novel KRASG12D inhibitor, MRTX1133, demonstrates promising antitumor efficacy in vitro and in vivo. However, the development of acquired resistance in treated patients presents a considerable challenge to sustained therapeutic effectiveness. In response to this challenge, we conducted site-specific mutagenesis screening to identify potential secondary mutations that could induce resistance to MRTX1133. We screened a range of KRASG12D variants harboring potential secondary mutations, and 44 representative variants were selected for in-depth validation of the pooled screening outcomes. We identified eight variants (G12D with V9E, V9W, V9Q, G13P, T58Y, R68G, Y96W, and Q99L) that exhibited substantial resistance, with V9W showing notable resistance, and downstream signaling analyses and structural modeling were conducted. We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

Keywords: Drug resistance; KRAS inhibitor; Site-specific mutagenesis screening

DOI: https://doi.org/10.1016/j.canlet.2024.216904

Expert Opin Ther Targets. 2024 Apr 22.

Strategies and techniques for preclinical therapeutic targeting of PI3Kin oncology: where do we stand in 2024?

Yanyan Liu, Qiu Sun, Xiawei Wei.

INTRODUCTION: The phosphatidylinositol-3-kinase (PI3K) pathway is a crucial intracellular signaling pathway involved in cell growth, proliferation, survival, and metabolism, which is aberrant in almost all types of cancer. Extensive research is dedicated to elucidating the mechanisms of action and developing PI3K inhibitors. However, only a small portion of the research has been successfully translated into clinical applications.
AREAS COVERED: In this review, we present an overview of the pivotal role that the PI3K pathway plays in tumor development. We discuss the current landscape of PI3K inhibitors in preclinical and clinical trials, address the mechanisms of resistance to PI3K inhibition along with their associated toxic effects, and highlight significant advancements in preclinical research of this field.
EXPERT OPINION: Based on our study and comprehension of PI3K, we provide a recapitulation of the key lessons learned from the research process and propose potential measures for improvement that could prove valuable.

Keywords: Cancer; PI3K; PI3K inhibitor; Preclinical research

DOI: https://doi.org/10.1080/14728222.2024.2342522

Nat Commun. 2024 Apr 26. 15(1): 3557

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.

Zhishan Chen, Xingyi Guo, Ran Tao, Jeroen R Huyghe, Philip J Law, Ceres Fernandez-Rozadilla, Jie Ping, Guochong Jia, Jirong Long, Chao Li, Quanhu Shen, Yuhan Xie, Maria N Timofeeva, Minta Thomas, Stephanie L Schmit, Virginia Díez-Obrero, Matthew Devall, Ferran Moratalla-Navarro, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah E W Briggs, Victoria Svinti, Kevin Donnelly, Susan M Farrington, James Blackmur, Peter G Vaughan-Shaw, Xiao-Ou Shu, Yingchang Lu, Peter Broderick, James Studd, Tabitha A Harrison, David V Conti, Fredrick R Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John L Hopper, Mark A Jenkins, Aung Ko Win, Rish K Pai, Jane C Figueiredo, Robert W Haile, Steven Gallinger, Michael O Woods, Polly A Newcomb, David Duggan, Jeremy P Cheadle, Richard Kaplan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Jukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri A Aaltonen, Harri Rissanen, Eero Pukkala, Johan G Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Satu Männistö, Demetrius Albanes, Stephanie J Weinstein, Edward Ruiz-Narvaez, Julie R Palmer, Daniel D Buchanan, Elizabeth A Platz, Kala Visvanathan, Cornelia M Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter T Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha L Slattery, John D Potter, Kostas K Tsilidis, Matthias B Schulze, Marc J Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, D Timothy Bishop, Graham G Giles, Melissa C Southey, Gregory E Idos, Kevin J McDonnell, Zomoroda Abu-Ful, Joel K Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope O Keku, Bethany van Guelpen, Thomas J Hudson, Heather Hampel, Rachel Pearlman, Sonja I Berndt, Richard B Hayes, Marie Elena Martinez, Sushma S Thomas, Paul D P Pharoah, Susanna C Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly F Doheny, Elizabeth Pugh, Tameka Shelford, Andrew T Chan, Marcia Cruz-Correa, Annika Lindblom, David J Hunter, Amit D Joshi, Clemens Schafmayer, Peter C Scacheri, Anshul Kundaje, Robert E Schoen, Jochen Hampe, Zsofia K Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Christopher K Edlund, W James Gauderman, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen J Chanock, Franzel van Duijnhoven, Edith J M Feskens, Lori C Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Barbara Pardini, Liesel M FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie A Bien, Charles Kooperberg, Christopher I Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Loic Le Marchand, Anna H Wu, Chenxu Qu, Caroline E McNeil, Gerhard Coetzee, Caroline Hayward, Ian J Deary, Sarah E Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Ken S Lau, Hongyu Zhao, Li Hsu, Qiuyin Cai, Malcolm G Dunlop, Stephen B Gruber, Richard S Houlston, Victor Moreno, Graham Casey, Ulrike Peters, Ian Tomlinson, Wei Zheng.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

DOI: https://doi.org/10.1038/s41467-024-47399-x

Cancer Sci. 2024 Apr 24.

The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/β-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Keywords: CD24; LAT1; amino acid transporter; mTOR; prostate cancer

DOI: https://doi.org/10.1111/cas.16191