The current development status of mitogen-activated protein kinase kinase (MEK) inhibitors, including the preclinical data and clinical study progress, has been summarized in this review. Different MEK inhibitors, possessing specific physicochemical properties and bioactivity characteristics, may provide different options for patients seeking treatment for cancer. Moreover, the combination of the MEK inhibitors with other therapies—such as chemotherapy, targeted therapy, and immunotherapy—may be a promising approach for clinical use.

Radiation‐induced intestinal injury is one of the major side effects in patients receiving radiation therapy. There is no specific treatment for radiation enteritis in the clinic. We designed and synthesized a new compound named XH‐105, which is expected to cleave into polyphenol and aminothiol in vivo to mitigate radiation injury. In the following study, we describe the beneficial effects of XH‐105 against radiation‐induced intestinal injury. C57BL/6J mice were treated by gavage with XH‐105 1 hour before total body irradiation (TBI), and the survival rate was monitored. Histological changes were examined, and survival of Lgr5⁺ intestinal stem cells Ki67⁺ cells, villi⁺ enterocytes and lysozymes was determined by immunohistochemistry. DNA damage and cellular apoptosis in intestinal tissue were also evaluated. Compared to vehicle‐treated mice after TBI, XH‐105 treatment significantly enhanced the survival rate, attenuated structural damage of the small intestine, decreased the apoptotic rate, reduced DNA damage, maintained cell regeneration and promoted crypt proliferation and differentiation. XH‐105 also reduced the expression of Bax and p53 in the small intestine. These data suggest that XH‐105 is beneficial for the protection of radiation‐induced intestinal injury by inhibiting the p53‐dependent apoptosis signalling pathway.

Background. Radiation‐induced intestinal injury is one of the side effects in patients receiving radiotherapy. The aim of the present study was to investigate the protective effect of XH‐103 on radiation‐induced small intestinal injury and to explore its mechanism. Methods. C57BL/6N mice were irradiated and treated with XH‐103. Firstly, the survival rate of mice exposed to 9.0 Gy and 11.0 Gy total body irradiation (TBI) was examined. Subsequently, at 3.5 d after IR, the small intestinal morphological changes were examined by HE. The numbers of crypt cells, the villus height, the expression of Ki67 and Lgr5, and the apoptotic cells in the intestinal crypts were examined by immunohistochemistry. Furthermore, the expression of p53 and Bax was analyzed by WB. Results. Compared to the irradiation group, XH‐103 improved the mice survival rate, protected the intestinal morphology of mice, decreased the apoptotic rate of intestinal crypt cells, maintained cell regeneration, and promoted crypt proliferation and differentiation. XH‐103 also reduced the expression of p53 and Bax in the small intestine compared to the IR group. Conclusion. These data demonstrate that XH‐103 can prevent radiation‐induced intestinal injury, which is beneficial for the protection of radiation injuries.

Purpose: Plexiform neurofibromas (PN) present a significant clinical challenge, with a notable unmet need for effective and well-tolerated therapies, particularly for the adult population. Patients and Methods: A single-arm, open-label, phase IIa trial of tunlametinib was conducted to assess its efficacy and safety in adults with inoperable, radiologically measurable PN. Patients received tunlametinib at a dose of 9 mg twice daily, following a continuous 21-day cycle regimen. The primary endpoint was the confirmed objective response rate (ORR), and secondary endpoints included disease control rate, duration of response, progression-free survival, and improvements in patient-reported outcomes (PRO) compared with baseline. Exploratory analyses integrating clinical variables and single-cell transcriptomic profiles were performed to explore response heterogeneity. Results: Of 15 adults (10 males and five females; median age, 27 years; range, 18–45), eight patients achieved a confirmed partial response, with an ORR of 53.3% (95% confidence interval, 26.69–78.73) and a median neurofibroma volume reduction of −23.5% (range, 1.6% to −49.1%). Significant improvements in multiple PRO domains were observed, including Patients’ Global Impression of Change and the Plexiform Neurofibromas Quality of Life scale. Regarding safety, all patients experienced at least one treatment-related adverse event, the majority of which were grade 1 or 2. Single-cell RNA sequencing profiling of pretreatment biopsies from one rapid responder and two gradual responders revealed substantial microenvironmental heterogeneity. Conclusions: Tunlametinib demonstrated promising efficacy and an acceptable safety profile in adults with PN, broadly aligning with the prior PN trials, including selumetinib and mirdametinib.

Purpose:Plexiform neurofibromas (PN) present a significant clinical challenge, with a notable unmet need for effective and well-tolerated therapies, particularly for the adult population.Patients and Methods:A single-arm, open-label, phase IIa trial of tunlametinib was conducted to assess its efficacy and safety in adults with inoperable, radiologically measurable PN. Patients received tunlametinib at a dose of 9 mg twice daily, following a continuous 21-day cycle regimen. The primary endpoint was the confirmed objective response rate (ORR), and secondary endpoints included disease control rate, duration of response, progression-free survival, and improvements in patient-reported outcomes (PRO) compared with baseline. Exploratory analyses integrating clinical variables and single-cell transcriptomic profiles were performed to explore response heterogeneity.Results:Of 15 adults (10 males and five females; median age, 27 years; range, 18–45), eight patients achieved a confirmed partial response, with an ORR of 53.3% (95% confidence interval, 26.69–78.73) and a median neurofibroma volume reduction of −23.5% (range, 1.6% to −49.1%). Significant improvements in multiple PRO domains were observed, including Patients’ Global Impression of Change and the Plexiform Neurofibromas Quality of Life scale. Regarding safety, all patients experienced at least one treatment-related adverse event, the majority of which were grade 1 or 2. Single-cell RNA sequencing profiling of pretreatment biopsies from one rapid responder and two gradual responders revealed substantial microenvironmental heterogeneity.Conclusions:Tunlametinib demonstrated promising efficacy and an acceptable safety profile in adults with PN, broadly aligning with the prior PN trials, including selumetinib and mirdametinib.