Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options.

P1, N=16, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2025 --> Jun 2026

P1/2, N=3, Terminated, National Cancer Institute (NCI) | Completed --> Terminated; Drug company withdrew support.

P1, N=52, Completed, University of Chicago | Recruiting --> Completed | N=100 --> 52 | Trial completion date: Dec 2026 --> Oct 2025 | Trial primary completion date: Jul 2026 --> Oct 2025

Furthermore, we found that, like OCI-AML cells, the exportin 1 (XPO1) inhibitors selinexor and eltanexor significantly induced cell cycle arrest and reduced PHGDH expression in OCI-AML3-OR cells. Therefore, treatment with PHGDH inhibitors could be a therapeutic strategy for refractory AML to PI3K/mTOR inhibitors. Relevant clinical trials are warranted.

P3, N=353, Active, not recruiting, Karyopharm Therapeutics Inc | Trial primary completion date: Sep 2025 --> Mar 2026 | Recruiting --> Active, not recruiting

P1, N=100, Recruiting, University of Chicago | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Jul 2025 --> Jul 2026

P1, N=16, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jun 2025 --> Dec 2025

Here, we show that the XPO1 nuclear export inhibitor eltanexor significantly reduces atherosclerotic plaque formation in a mouse model of Tet2 -mutant CHIP...Tet2 loss diminished ATF3 binding to the regulatory loci of inflammatory mediators, which was restored upon XPO1 inhibition. These results provide new insights into drivers of heightened inflammation in TET2 -mutant CHIP and highlight a novel therapeutic strategy for intervention.

Drug sensitivity assays using organoids from Apcmin/+ mice tumors show increased sensitivity to Eltanexor compared to wild-type organoids. Collectively, these findings highlight XPO1 as a potent target for CRC chemoprevention.

Our study elucidated that EP300 inhibition, especially in combination with XPO1 blockade, could serve as a promising therapeutic strategy for the treatment of DLBCL.