It is reported that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway, and M1C drives the sotorasib resistant phenotype by NF-κB-mediated induction of the epithelial-mesenchymal transition and a mucinous gene program.
Abstract
Treatment of NSCLC KRAS G12C mutant tumors with the allele-selective sotorasib and adagrasib inhibitors is invariably associated with acquired resistance. The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway. In turn, M1C drives the sotorasib resistant phenotype by NF-κB-mediated induction of the epithelial-mesenchymal transition (EMT) and a mucinous gene program. Targeting M1C→NF-κB signaling (i) suppresses EMT and mucin genes, and (ii) reverses sotorasib resistance. Of translational relevance, treatment with a M1C antibody-drug conjugate (ADC) is effective against two sotorasib-resistant NSCLC KRAS G12C cell lines and two patient-derived tumor xenograft models. Analysis of patients with NSCLC KRAS G12C tumors treated with sotorasib/adagrasib and overexpressing MUC1 associates with decreases in overall survival. These findings identify M1C as a key effector of sotorasib resistance and as a target for treatment of patients with refractory NSCLC KRAS G12C mutant tumors.
Background KRAS G12C-mutant advanced non-small cell lung cancer (NSCLC) is currently treated with KRAS G12C covalent inhibitors, such as sotorasib, or RAS (ON) G12-selective inhibitors; however, response rates and progression-free survival remain limited, with recurrence occurring in most patients. Although mechanisms of resistance in KRAS G12C cell lines are multifarious, they have been attributed to EGFR activation and Aurora kinase A (AURKA) signaling via Ras-related nuclear protein (Ran). Ran-GTP cooperates with Exportin-1 (XPO1), which has been identified as essential in KRAS-mutant NSCLC cells. Methods KRAS G12C NSCLC cell lines, including H2030, which is resistant to sotorasib (KRAS G12C inhibitor) and selinexor (XPO1 inhibitor), were treated with sotorasib plus selinexor following pretreatment with omeprazole (a V-ATPase proton pump inhibitor) to assess effects on cell viability and protein expression. An in vivo study was also conducted using a KRAS G12C H2030 cell-derived tumor xenograft model. Results The combination of omeprazole with sotorasib and selinexor almost completely suppressed colony formation in the KRAS G12C-mutant cell lines tested (NCI-H358, NCI-H23, NCI-H2030, and NCI-H358R). While sotorasib did not influence XPO1 protein expression in any of the cell lines, the combination of selinexor, omeprazole and sotorasib completely suppressed XPO1 expression, as well as AURKA, survivin, YAP1, MRAS, and other key proteins. In the H2030 xenograft model, tumor growth was significantly inhibited by treatment with the three-drug combination of omeprazole, sotorasib, and selinexor, with no apparent toxic side-effects or weight loss observed. Conclusions XPO1 protein suppression is not achieved with sotorasib alone in KRAS G12C NSCLC cells. Notably, the combination of sotorasib, selinexor, and omeprazole abolishes the expression of XPO1, AURKA, YAP, and MRAS. The feasibility of therapy with XPO1 inhibition plus KRAS inhibitors warrants clinical exploration.
The in vitro proliferation of AKP-M4 cells, but not KRAS wild-type SNU-1079 and SSP-25 cells, was reduced by the KRAS G12D mutation inhibitor MRTX-1133, which supports the development of KRAS mutation inhibitor for CCA treatment.
J. Hung, Tsai-Hsien Hung, Chun-Nan Yeh et al.· Journal of Immunology· 0 citations
This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.
Xizhi Zha· Theoretical and Natural Scie...· 0 citations
In contrast to non-small cell lung cancer and pancreatic cancer, KRAS inhibitors exhibited limited single agent activities in colorectal cancer (CRC), largely owing to EGFR-mediated adaptive MAPK pathway reactivation and intratumor heterogeneity. JAB-BX600, a humanized, EGFR-targeted antibody-drug conjugate (ADC) with a KRAS G12D inhibitor (JAB-22G82) as payload with a drug-to-antibody ratio (DAR) of 8, represents a revolutionary module for synergistic dual-node signaling blockade. In the current study, the therapeutic potential of JAB-BX600 in CRC and other solid tumors including PDAC with KRAS G12D mutation was evaluated.
The KRAS G12D inhibitor JAB-22G82 used as ADC payload was developed through Jacobio’s proprietary Induced Allosteric Drug Discovery Platform (IADDP). The binding affinity of JAB-22G82 for GDP-KRAS G12D was determined by SPR. The internalization efficacy of JAB-BX600 was evaluated by flow cytometry. The inhibitory effect of both JAB-22G82 and JAB-BX600 on cell viability was evaluated by a luminescence-based assay. The plasma stability of JAB-BX600 across species was evaluated by LC-MS/MS. In vivo anti-tumor efficacy of JAB-BX600 was evaluated in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. The pharmacokinetics (PK) and safety profiles of JAB-BX600 in cynomolgus monkeys were obtained.
The KRAS G12D inhibitor JAB-22G82 (payload) exhibited high binding affinity for KRAS G12D with KD of 14.5 fM, and high potency to inhibit cell viability with subnanomolar IC50s in most KRAS G12D mutant tumor cells tested. JAB-BX600 and the unconjugated EGFR antibody exhibited comparable potent EGFR binding, efficient internalization, and antibody-dependent cellular cytotoxicity (ADCC) induction in tumor cells. Remarkably, JAB-BX600 inhibited cell viability with IC50s at the 10 pM level across most tumor cell lines tested, and exhibited >2000-fold selectivity against normal human skin cells, indicating less skin toxicity. A single administration of JAB-BX600 at 3 mg/kg induced tumor regression in both CRC and PDAC animal models, with high intratumoral payload distribution and minimal payload release in plasma. Finally, JAB-BX600 with dosing up to 60 mg/kg exhibited an overall favorable tolerability profile in cynomolgus monkeys.
JAB-BX600 exhibits potent anti-tumor activity in KRAS G12D-mutant tumor models and a favorable preclinical safety profile. These results support further clinical development of JAB-BX600 as a promising therapeutic strategy for KRAS G12D-driven cancers, particularly CRC and PDAC. The IND will be submitted in 2026.
Peng Wang, Fangjie Liu, Xiaoyu Liu, Haijun Li, Xueting He, Amin Li, Andrea Wang-Gillam, Xin Sun, Yiwei Lin, Yanping Wang. JAB-BX600, a first-in-class EGFR-directed antiboEdy drug conjugate delivering a novel KRAS G12D inhibitor [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr PR005.
Peng Wang, Fangjie Liu, Xiaoyu Liu et al.· Clinical Cancer Research· 0 citations
In contrast to non-small cell lung cancer and pancreatic cancer, KRAS inhibitors exhibited limited single agent activities in colorectal cancer (CRC), largely owing to EGFR-mediated adaptive MAPK pathway reactivation and intratumor heterogeneity. JAB-BX600, a humanized, EGFR-targeted antibody-drug conjugate (ADC) with a KRAS G12D inhibitor (JAB-22G82) as payload with a drug-to-antibody ratio (DAR) of 8, represents a revolutionary module for synergistic dual-node signaling blockade. In the current study, the therapeutic potential of JAB-BX600 in CRC and other solid tumors including PDAC with KRAS G12D mutation was evaluated.
The KRAS G12D inhibitor JAB-22G82 used as ADC payload was developed through Jacobio’s proprietary Induced Allosteric Drug Discovery Platform (IADDP). The binding affinity of JAB-22G82 for GDP-KRAS G12D was determined by SPR. The internalization efficacy of JAB-BX600 was evaluated by flow cytometry. The inhibitory effect of both JAB-22G82 and JAB-BX600 on cell viability was evaluated by a luminescence-based assay. The plasma stability of JAB-BX600 across species was evaluated by LC-MS/MS. In vivo anti-tumor efficacy of JAB-BX600 was evaluated in both cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. The pharmacokinetics (PK) and safety profiles of JAB-BX600 in cynomolgus monkeys were obtained.
The KRAS G12D inhibitor JAB-22G82 (payload) exhibited high binding affinity for KRAS G12D with KD of 14.5 fM, and high potency to inhibit cell viability with subnanomolar IC50s in most KRAS G12D mutant tumor cells tested. JAB-BX600 and the unconjugated EGFR antibody exhibited comparable potent EGFR binding, efficient internalization, and antibody-dependent cellular cytotoxicity (ADCC) induction in tumor cells. Remarkably, JAB-BX600 inhibited cell viability with IC50s at the 10 pM level across most tumor cell lines tested, and exhibited >2000-fold selectivity against normal human skin cells, indicating less skin toxicity. A single administration of JAB-BX600 at 3 mg/kg induced tumor regression in both CRC and PDAC animal models, with high intratumoral payload distribution and minimal payload release in plasma. Finally, JAB-BX600 with dosing up to 60 mg/kg exhibited an overall favorable tolerability profile in cynomolgus monkeys.
JAB-BX600 exhibits potent anti-tumor activity in KRAS G12D-mutant tumor models and a favorable preclinical safety profile. These results support further clinical development of JAB-BX600 as a promising therapeutic strategy for KRAS G12D-driven cancers, particularly CRC and PDAC. The IND will be submitted in 2026.
Peng Wang, Fangjie Liu, Xiaoyu Liu, Haijun Li, Xueting He, Amin Li, Andrea Wang-Gillam, Xin Sun, Yiwei Lin, Yanping Wang. JAB-BX600, a first-in-class EGFR-directed antiboEdy drug conjugate delivering a novel KRAS G12D inhibitor [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A015.
Peng Wang, Fangjie Liu, Xiaoyu Liu et al.· Clinical Cancer Research· 0 citations
KRASG12D-selective and pan-RAS inhibitors have shown promise in pancreatic ductal adenocarcinoma (PDAC), yet adaptive resistance is anticipated to limit durability of response. Exportin 1 (XPO1), a nuclear export protein frequently overexpressed in PDAC, represents a potential vulnerability in KRAS-mutant cancers. We evaluated whether pharmacologic inhibition of XPO1 enhances therapeutic efficacy and durability of KRAS pathway inhibition. KRASG12D inhibitor- and pan-RAS inhibitor-resistant PDAC cellular models were generated and assessed for sensitivity to the second-generation XPO1 inhibitor Eltanexor. Antiproliferative synergistic effects of Eltanexor combined with MRTX1133, Zoldonrasib (RMC9805), or Daraxonrasib (RMC6236) were evaluated in PDAC 2D cultures, 3D spheroids, patient-derived organoids, and tumor-fibroblast co-culture models. Eltanexor sensitized KRAS inhibitor-resistant PDAC cells and synergistically enhanced growth suppression across multiple KRASG12D-mutant models. Combination treatment reduced clonogenic survival, disrupted 3D spheroid integrity, and significantly inhibited viability of patient-derived organoids. The in vivo efficacy of the combination was tested in PDAC cell-derived xenograft/allograft and patient-derived xenograft models. Combining sub-therapeutic doses of Eltanexor with allele-specific inhibitors or pan-RASi resulted in significant tumor regression, prevention of metastatic spread and prolonged survival in vivo. Notably, Eltanexor maintenance therapy suppressed tumor regrowth following RAS inhibitor withdrawal and preserved responsiveness upon re-challenge. Mechanistically, molecular and phosphokinome profiling showed that the combination broadened suppression of MAPK- and mTOR-associated signaling and reduced activity of multiple oncogenic kinases. In conclusion, XPO1 inhibitor Eltanexor enhances the efficacy and durability of KRAS and pan-RAS inhibition in PDAC models. These findings provide a preclinical rationale for clinically evaluating Eltanexor in combination with RAS-targeted therapies to delay or overcome adaptive resistance in KRAS-mutant PDAC.
H. Y. Khan, M. Al-Hallak, A. Aboukameel et al.· Cancer Letters· 0 citations
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