bims-pimaco 2024-05-19 papers

Issue of 2024‒05‒19
five papers selected by
Lucas B. Zeiger

Front Oncol. 2024 ;14 1380584

KRAS G12C inhibitor combination therapies: current evidence and challenge.

Hirotaka Miyashita, Shumei Kato, David S Hong.

Although KRAS G12C inhibitors have proven that KRAS is a "druggable" target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

Keywords: KRAS; KRAS G12C inhibitors; MAPK; RTK inhibitors; combination (combined) therapy; immunotherapy; mTOR

DOI: https://doi.org/10.3389/fonc.2024.1380584

Elife. 2024 May 13. pii: RP92236. [Epub ahead of print]12

mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated ubiquitination of eIF4A1 in cancer cells.

Dongyue Jiao, Huiru Sun, Xiaying Zhao, Yingji Chen, Zeheng Lv, Qing Shi, Yao Li, Chenji Wang, Kun Gao.

Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of the Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by the CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and cervical tumor cell growth both in vivo and in vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.

Keywords: cancer biology; cell biology; human; mTORC1/S6K1 signaling; phosphorylation; translation; tumorigenesis; ubiquitination

DOI: https://doi.org/10.7554/eLife.92236

Autophagy. 2024 May 14.

Unexpected roles for AMPK in the suppression of autophagy and the reactivation of MTORC1 signaling during prolonged amino acid deprivation.

Dubek Kazyken, Sydney G Dame, Claudia Wang, Maxwell Wadley, Diane C Fingar.

AMPK promotes catabolic and suppresses anabolic cell metabolism to promote cell survival during energetic stress, in part by inhibiting MTORC1, an anabolic kinase requiring sufficient levels of amino acids. We found that cells lacking AMPK displayed increased apoptotic cell death during nutrient stress caused by prolonged amino acid deprivation. We presumed that impaired macroautophagy/autophagy explained this phenotype, as a prevailing view posits that AMPK initiates autophagy (often a pro-survival response) through phosphorylation of ULK1. Unexpectedly, however, autophagy remained unimpaired in cells lacking AMPK, as monitored by several autophagic readouts in several cell lines. More surprisingly, the absence of AMPK increased ULK1 signaling and MAP1LC3B/LC3B lipidation during amino acid deprivation while AMPK-mediated phosphorylation of ULK1 S555 (a site proposed to initiate autophagy) decreased upon amino acid withdrawal or pharmacological MTORC1 inhibition. In addition, activation of AMPK with compound 991, glucose deprivation, or AICAR blunted autophagy induced by amino acid withdrawal. These results demonstrate that AMPK activation and glucose deprivation suppress autophagy. As AMPK controlled autophagy in an unexpected direction, we examined how AMPK controls MTORC1 signaling. Paradoxically, we observed impaired reactivation of MTORC1 in cells lacking AMPK upon prolonged amino acid deprivation. Together these results oppose established views that AMPK promotes autophagy and inhibits MTORC1 universally. Moreover, they reveal unexpected roles for AMPK in the suppression of autophagy and the support of MTORC1 signaling in the context of prolonged amino acid deprivation. These findings prompt a reevaluation of how AMPK and its control of autophagy and MTORC1 affect health and disease.

Keywords: ATG16L1; EIF4EBP1/4EBP1; LC3B; MTOR; RPS6KB1/S6K1; ULK1

DOI: https://doi.org/10.1080/15548627.2024.2355074

Nat Commun. 2024 May 14. 15(1): 4083

mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.

Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.

DOI: https://doi.org/10.1038/s41467-024-48386-y

Nat Commun. 2024 May 15. 15(1): 4114

IRE1α determines ferroptosis sensitivity through regulation of glutathione synthesis.

Dadi Jiang, Youming Guo, Tianyu Wang, Liang Wang, Yuelong Yan, Ling Xia, Rakesh Bam, Zhifen Yang, Hyemin Lee, Takao Iwawaki, Boyi Gan, Albert C Koong.

Cellular sensitivity to ferroptosis is primarily regulated by mechanisms mediating lipid hydroperoxide detoxification. We show that inositol-requiring enzyme 1 (IRE1α), an endoplasmic reticulum (ER) resident protein critical for the unfolded protein response (UPR), also determines cellular sensitivity to ferroptosis. Cancer and normal cells depleted of IRE1α gain resistance to ferroptosis, while enhanced IRE1α expression promotes sensitivity to ferroptosis. Mechanistically, IRE1α's endoribonuclease activity cleaves and down-regulates the mRNA of key glutathione biosynthesis regulators glutamate-cysteine ligase catalytic subunit (GCLC) and solute carrier family 7 member 11 (SLC7A11). This activity of IRE1α is independent of its role in regulating the UPR and is evolutionarily conserved. Genetic deficiency and pharmacological inhibition of IRE1α have similar effects in inhibiting ferroptosis and reducing renal ischemia-reperfusion injury in mice. Our findings reveal a previously unidentified role of IRE1α to regulate ferroptosis and suggests inhibition of IRE1α as a promising therapeutic strategy to mitigate ferroptosis-associated pathological conditions.

DOI: https://doi.org/10.1038/s41467-024-48330-0