bims-pimaco 2024-08-04 papers

Issue of 2024–08–04
six papers selected by
Lucas B. Zeiger

Mol Cancer Ther. 2024 Aug 01.

Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers.

Fei Xiao, Kailiang Wang, Xinjuan Wang, Huijuan Li, Zhilong Hu, Xiaoming Ren, Wei Huang, Teng Feng, Lili Yao, Jing Lin, Chunlai Li, Zhuanzhuan Zhang, Liufeng Mei, Xiaotian Zhu, Wenge Zhong, Zhi Xie.

KRAS is the most frequently dysregulated oncogene with high prevalence in NSCLC, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein SOS1. SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single digit nM potency and is highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combination with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0049

Mol Oncol. 2024 Aug 02.

Assessments of prostate cancer cell functions highlight differences between a pan-PI3K/mTOR inhibitor, gedatolisib, and single-node inhibitors of the PI3K/AKT/mTOR pathway.

Adrish Sen, Salmaan Khan, Stefano Rossetti, Aaron Broege, Ian MacNeil, Ann DeLaForest, Jhomary Molden, Laura Davis, Charles Iversrud, Megan Seibel, Ross Kopher, Stephen Schulz, Lance Laing.

Metastatic castration-resistant prostate cancer (mCRPC) is characterized by loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway. Loss of the PI3K regulator PTEN is frequent during prostate cancer (PC) initiation, progression, and therapeutic resistance. Co-targeting the PAM/AR pathways is a promising mCRPC treatment strategy but is hampered by reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors selectively spare (or weakly inhibit) one or more key nodes of the PAM pathway, potentiating drug resistance depending on the PAM pathway mutation status of patients. We posited that gedatolisib, a uniformly potent inhibitor of all class I PI3K isoforms, as well as mTORC1 and mTORC2, would be more effective than inhibitors targeting single PAM pathway nodes in PC cells. Using a combination of functional and metabolic assays, we evaluated a panel of PC cell lines with different PTEN/PIK3CA status for their sensitivity to multi-node PAM inhibitors (PI3K/mTOR: gedatolisib, samotolisib) and single-node PAM inhibitors (PI3Kα: alpelisib; AKT: capivasertib; mTOR: everolimus). Gedatolisib induced anti-proliferative and cytotoxic effects with greater potency and efficacy relative to the other PAM inhibitors, independent of PTEN/PIK3CA status. The superior effects of gedatolisib were likely associated with more effective inhibition of critical PAM-controlled cell functions, including cell cycle, survival, protein synthesis, oxygen consumption rate, and glycolysis. Our results indicate that potent and simultaneous blockade of all class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN-dependent resistance. Gedatolisib, as a single agent and in combination with other therapies, reported promising preliminary efficacy and safety in various solid tumor types. Gedatolisib is currently being evaluated in a Phase 1/2 clinical trial in combination with darolutamide in patients with mCRPC previously treated with an AR inhibitor, and in a Phase 3 clinical trial in combination with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer.

Keywords: PI3K/AKT/mTOR pathway; gedatolisib; inhibitors; prostate cancer

DOI: https://doi.org/10.1002/1878-0261.13703

Cell Rep. 2024 Jul 26. pii: S2211-1247(24)00872-6. [Epub ahead of print]43(8): 114543

mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction.

Jay N Joshi, Ariel D Lerner, Frank Scallo, Alexandra N Grumet, Paul Matteson, James H Millonig, Alexander J Valvezan.

Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that is active in nearly all proliferating eukaryotic cells; however, it is unclear whether mTORC1 activity changes throughout the cell cycle. We find that mTORC1 activity oscillates from lowest in mitosis/G1 to highest in S/G2. The interphase oscillation is mediated through the TSC complex but is independent of major known regulatory inputs, including Akt and Mek/Erk signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex. mTORC1 has long been known to promote progression through G1. We find that mTORC1 also promotes progression through S and G2 and is important for satisfying the Chk1/Wee1-dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together, these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific consequences for proliferating cells.

Keywords: CDK1; CP: Cell biology; G2/M checkpoint; TSC complex; TSC2; autophagy; cell cycle; mTOR; mTORC1; mitosis

DOI: https://doi.org/10.1016/j.celrep.2024.114543

Expert Opin Drug Saf. 2024 Jul 31.

Post-marketing safety concern of PI3K inhibitors in the cancer therapies: an 8-year disproportionality analysis from the FDA adverse event reporting system.

Lisha Wu, Hongyan Huang, Yimin Zhang, Wei Zhuang, Xiaorong Lin.

BACKGROUND: ThePhosphoinositide 3-kinases (PI3Ks) family plays a crucial role intumorigenesis. Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibitingPI3Kδ) were developed to target the PI3K pathway. However, the toxicity limitstheir application to some extent. It's necessary to investigate the adverseeffects (AEs) of these inhibitors.
RESEARCH DESIGNAND METHODS: We conducted acomparative analysis of the safety signals of AEs in PI3K inhibitors usingdisproportionality analysis in the FDA Adverse Event Reporting System database(FAERS).
RESULTS: Our studyidentified significant safety signals for metabolic disorders with all PI3Kinhibitors. Notable safety signals for gastrointestinal disorders were observedwith most PI3K inhibitors, with the exception of copanlisib. Common AEs shared amongall PI3K inhibitors included colitis and dehydration. Alpelisib displayedunique AEs associated with metabolic disorders, whereas copanlisib exhibitedidiosyncratic AEs linked to cardiac and vascular disorders. Stevens-Johnsonsyndrome emerged as a common severe adverse event (SAE) among alpelisib,copanlisib, and idelalisib, while febrile neutropenia was prevalent amongcopanlisib, duvelisib, and idelalisib. Intestinal perforation was solelyassociated with alpelisib.
CONCLUSIONS: The safety profiles of the five PI3K inhibitorsvary concerning adverse events. These findings could guide drug selection andinform future prospective research.

Keywords: FAERS; Phosphoinositide 3-kinase inhibitors; adverse events; alpelisib; copanlisib; disproportionality analysis; duvelisib; idelalisib; umbralisib

DOI: https://doi.org/10.1080/14740338.2024.2387317

Elife. 2024 Jul 31. pii: RP92822. [Epub ahead of print]12

Structural and dynamic changes in P-Rex1 upon activation by PIP3 and inhibition by IP4.

Sandeep K Ravala, Sendi Rafael Adame-Garcia, Sheng Li, Chun-Liang Chen, Michael A Cianfrocco, J Silvio Gutkind, Jennifer N Cash, John J G Tesmer.

PIP3-dependent Rac exchanger 1 (P-Rex1) is abundantly expressed in neutrophils and plays central roles in chemotaxis and cancer metastasis by serving as a guanine-nucleotide exchange factor (GEF) for Rac. The enzyme is synergistically activated by PIP3 and heterotrimeric Gβγ subunits, but mechanistic details remain poorly understood. While investigating the regulation of P-Rex1 by PIP3, we discovered that Ins(1,3,4,5)P4 (IP4) inhibits P-Rex1 activity and induces large decreases in backbone dynamics in diverse regions of the protein. Cryo-electron microscopy analysis of the P-Rex1·IP4 complex revealed a conformation wherein the pleckstrin homology (PH) domain occludes the active site of the Dbl homology (DH) domain. This configuration is stabilized by interactions between the first DEP domain (DEP1) and the DH domain and between the PH domain and a 4-helix bundle (4HB) subdomain that extends from the C-terminal domain of P-Rex1. Disruption of the DH-DEP1 interface in a DH/PH-DEP1 fragment enhanced activity and led to a more extended conformation in solution, whereas mutations that constrain the occluded conformation led to decreased GEF activity. Variants of full-length P-Rex1 in which the DH-DEP1 and PH-4HB interfaces were disturbed exhibited enhanced activity during chemokine-induced cell migration, confirming that the observed structure represents the autoinhibited state in living cells. Interactions with PIP3-containing liposomes led to disruption of these interfaces and increased dynamics protein-wide. Our results further suggest that inositol phosphates such as IP4 help to inhibit basal P-Rex1 activity in neutrophils, similar to their inhibitory effects on phosphatidylinositol-3-kinase.

Keywords: E. coli; PIP3; RhoGEF; biochemistry; chemical biology; cryo-EM; molecular biophysics; signaling; structural biology

DOI: https://doi.org/10.7554/eLife.92822

Nat Cell Biol. 2024 Jul 30.

mTORC2-driven chromatin cGAS mediates chemoresistance through epigenetic reprogramming in colorectal cancer.

Guoqing Lv, Qian Wang, Lin Lin, Qiao Ye, Xi Li, Qian Zhou, Xiangzhen Kong, Hongxia Deng, Fuping You, Hebing Chen, Song Wu, Lin Yuan.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2-ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells.

DOI: https://doi.org/10.1038/s41556-024-01473-0