KRAS expression

Importantly, cells in which recombination has successfully occurred can be visualized and isolated using the fluorescence emitted by tdTomato. Furthermore, we show that KRASG12D production enables intestinal organoid growth independent of epidermal growth factor (EGF) signaling and that the KRASG12D function is effectively suppressed by specific inhibitor MRTX1133.

To determine the sensitivity of KRAS or/and TP53-mutated cancer to KRAS, MEK1, or PLK1-targeted therapy, the inhibitors salirasib, trametinib, volasertib, and onvansertib were used in COAD cells with different KRAS and TP53 status. This treatment induced G1 and G2/M arrest, respectively, and showed the strongest synergistic effect in KRAS and TP53-mutated SW48 cells expressing mutant KRASG13D and transduced with TP53 shRNA, ultimately leading to apoptotic cell death. These effects are attributed to two-step inhibition mechanism that blocks the MAPK signaling pathway and disrupts mitosis in KRAS and TP53-mutated COAD cells.

SIGLEC9 expression was significantly associated with the expression of multiple cytokines, chemokines, and growth factors in the CRC TME. These associations suggest the significant potential of SIGLEC9 as a molecule that plays a crucial role in shaping the immune properties of the CRC TME, as well as its potential therapeutic relevance, particularly in the group of high-grade CRC tumors.

Although we have shown that the 3D environment dramatically sensitizes cells to MRTX1133 treatment, the synergistic effect of this drug combination is present in both 2D and 3D in the PANC1 pancreatic adenocarcinoma model, which showed high resistance to MRTX1133 in 2D. The effects of the combination treatment show an association with the inhibition of farnesylated regulatory proteins, including HRAS and RHEB, along with the expression level of KRAS. Our study warrants further investigation for the potential applicability of KRAS G12D inhibitors in combination with farnesyl-transferase inhibitors for the treatment of KRAS mutant pancreatic adenocarcinoma.

Finally, we demonstrate that HNF4α depletion enhances sensitivity to pharmacologic KRAS G12D inhibition. Collectively, our data show that co-expression of opposing lineage specifiers leads to a hybrid identity state that can drive tumor progression and dictate response to targeted therapy in LUAD.

Exposure to the non-selective beta adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551 blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. We show that SIS induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in KC mice subjected to an obesogenic HFCD. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.

In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in Phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer (NSCLC).

Treatment with the KRasG12C-specific inhibitor, ARS-1620, significantly increased IDO1 expression, which inversely correlated with PD-L1 expression in the KRasG12C-mutant H358 cell line...Moreover, the induction of IDO1 expression following KRas inhibition appears to operate independently of the MAPK pathway. Our results propose that concurrent targeting of KRas and IDO1 could potentiate therapeutic efficacy in KRas-mutant cancers, overcoming resistance to immune checkpoint blockade.

Our study shows miR-196a-5p has reasonable specificity to PC and thus may have diagnostic and prognostic potential in PC as proposed in the literature. Moreover, KRAS and NFKBIA may be potential targets for miR-217-5p and miR-196a-5p, respectively. Thus, these miRNAs may be involved in tumor progression and may have valuable applications in novel therapeutics or treatment monitoring.

This suggests a potential mechanism explaining the increased sensitivity of CRC cells harboring a KRAS-activated pathway to acetate. These findings contribute to a clearer understanding of how KRAS regulate BAX function, a relevant aspect in tumor progression.

Mechanistically, TMOD3 promoted F-actin polymerization, thereby facilitating the fusion of autophagosomes with lysosomes, increasing the degradation of the ACSL4 protein, and augmenting the ferroptosis-inducing effects of RSL3...Cangrelor, an FDA-approved drug, can target TMOD3...In conclusion, TMOD3 was found to inhibit ferroptosis and induced the resistance to PD-1 antibody by facilitating the fusion of autophagosomes and lysosomes through the promotion of F-actin polymerization in KRAS-mutant PC. TMOD3 was identified as a novel target for PC therapy.

Its versatility has enabled the development of diverse cancer models including liver, pancreatic, lung, and bladder cancer. Serving as a clinically relevant model for human cancer, the Oncopig addresses unmet clinical needs and holds immense promise for advancing preclinical cancer research and therapeutic development.