bims-pimaco 2023-09-24 papers

Issue of 2023‒09‒24
four papers selected by
Lucas B. Zeiger, Beatson Institute for Cancer Research

ACS Med Chem Lett. 2023 Sep 14. 14(9): 1138-1140

New Horizons in Cancer Treatment: A Closer Look at Novel PI3Kα Inhibitors.

Phosphoinositide 3-kinase (PI3K), a lipid messenger in cellular biology, regulates numerous cellular responses, including cell survival and migration. Abnormal activation of PI3K has been identified in many human tumors, implicating it as a pivotal point in cancer research. PI3K inhibitors have shown promise in controlling tumor progression and chemotherapy resistance. However, challenges like cutaneous adverse effects require further research. The PI3K signaling pathway's role in cellular processes, such as aging and Alzheimer's disease progression, also signifies its importance in drug development for aging-related diseases. Future research promises innovative therapeutic strategies targeting PI3K in managing cancer, aging, and neurodegenerative diseases. This Patent Highlight showcases compounds and compositions that may enlarge the PI3K inhibitory therapeutic window-effectively inhibiting the target in cancer cells while reducing toxicity in patients.

DOI: https://doi.org/10.1021/acsmedchemlett.3c00307

Mol Biol Cell. 2023 Sep 20. mbcE23050152

CRISPR-mediated reversion of oncogenic KRAS mutation results in increased proliferation and reveals independent roles of Ras and mTORC2 in the migration of A549 lung cancer cells.

Alyssa N Werner, Avani I Kumar, Pascale G Charest.

Although the RAS oncogene has been extensively studied, new aspects concerning its role and regulation in normal biology and cancer continue to be discovered. Recently, others and we have shown that the mechanistic Target of Rapamycin Complex 2 (mTORC2) is a Ras effector in Dictyostelium and mammalian cells. mTORC2 plays evolutionarily conserved roles in cell survival and migration and has been linked to tumorigenesis. Since RAS is often mutated in lung cancer, we investigated whether a Ras-mTORC2 pathway contributes to enhancing the migration of lung cancer cells expressing oncogenic Ras. We used A549 cells and CRISPR/Cas9 to revert the cells' KRAS G12S mutation to wild-type and establish A549 revertant (REV) cell lines, which we then used to evaluate the Ras-mediated regulation of mTORC2 and cell migration. Interestingly, our results suggest that K-Ras and mTORC2 promote A549 cell migration but as part of different pathways and independently of Ras's mutational status. Moreover, further characterization of the A549REV cells revealed that loss of mutant K-Ras expression for the wild-type protein leads to an increase in cell growth and proliferation, suggesting that the A549 cells have low KRAS mutant dependency and that recovering expression of wild-type K-Ras protein increases these cells tumorigenic potential.

DOI: https://doi.org/10.1091/mbc.E23-05-0152

Cell Mol Life Sci. 2023 Sep 16. 80(10): 292

Reciprocal negative feedback regulation of ATF6α and PTEN promotes prostate cancer progression.

Tingting Feng, Ru Zhao, Hanwen Zhang, Feifei Sun, Jing Hu, Meng Wang, Mei Qi, Ling Liu, Lin Gao, Yabo Xiao, Junhui Zhen, Weiwen Chen, Lin Wang, Bo Han.

Phosphatase and tensin homolog (PTEN) loss tightly correlates with prostate cancer (PCa) progression and metastasis. Inactivation of PTEN leads to abnormal activation of PI3K/AKT pathway. However, results from clinical trials with AKT inhibitors in PCa have been largely disappointing. Identification of novel regulators of PTEN in PTEN-dysfunctional PCa is urgently needed. Here we demonstrated that the expression level of PTEN is inversely correlated with the signature score of unfolded protein response (UPR) in PCa. Importantly, PTEN suppresses the activity of ATF6α, via interacting to de-phosphorylate ATF6α and consequently inhibiting its nuclear translocation. Conversely, ATF6α promotes the ubiquitination and degradation of PTEN by inducing CHIP expression. Thus, ATF6α and PTEN forms a negative feedback loop during PCa progression. Combination of ATF6α inhibitor with AKT inhibitor suppresses tumor cell proliferation and xenograft growth. Importantly, this study highlighted ATF6α as a therapeutic vulnerability in PTEN dysfunctional PCa.

Keywords: ATF6α; PTEN; Prostate cancer; UPR

DOI: https://doi.org/10.1007/s00018-023-04940-3

Int J Gen Med. 2023 ;16 4109-4120

KRAS/NRAS Mutations Associated with Distant Metastasis and BRAF/PIK3CA Mutations Associated with Poor Tumor Differentiation in Colorectal Cancer.

Juanzi Zeng, Wenwei Fan, Jiaquan Li, Guowu Wu, Heming Wu.

Background: The occurrence, progression, and prognosis of colorectal cancer (CRC) are regulated by EGFR-mediated signaling pathways. However, the relationship between the core genes (KRAS/NRAS/BRAF/PIK3CA) status in the signaling pathways and clinicopathological characteristics of CRC patients in Hakka population remains controversial.Methods: Patients were genotyped for KRAS (codons 12, 13, 61, 117, and 146), NRAS (codons 12, 61, 117, and 146), BRAF (codons 600), and PIK3CA (codons 542, 545 and 1047) mutations. Clinical records were collected, and clinicopathological characteristic associations were analyzed together with mutations of studied genes.
Results: Four hundred and eight patients (256 men and 152 women) were included in the analysis. At least one mutation in the four genes was detected in 216 (52.9%) patients, while none was detected in 192 (47.1%) patients. KRAS, NRAS, BRAF, and PIK3CA mutation status were detected in 190 (46.6%), 11 (2.7%), 10 (2.5%), 34 (8.3%) samples, respectively. KRAS exon 2 had the highest proportion (62.5%). Age, tumor site, tumor size, lymphovascular invasion, and perineural invasion were not associated with gene mutations. KRAS mutations (adjusted OR 1.675, 95% CI 1.017-2.760, P=0.043) and NRAS mutations (adjusted OR 5.183, 95% CI 1.239-21.687, P=0.024) appeared more frequently in patients with distant metastasis. BRAF mutations (adjusted OR 7.224, 95% CI 1.356-38.488, P=0.021) and PIK3CA mutations (adjusted OR 3.811, 95% CI 1.268-11.455, P=0.017) associated with poorly differentiated tumor.
Conclusion: KRAS/NRAS mutations are associated with distant metastasis and BRAF/PIK3CA mutations are associated with poor tumor differentiation in CRC. And the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients.

Keywords: BRAF; KRAS; NRAS; PIK3CA; clinicopathological feature; colorectal cancer

DOI: https://doi.org/10.2147/IJGM.S428580