BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with occupational asbestos exposure, arising from malignant transformation of mesothelial cells in the parietal pleura. For 20 years, chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care; however, prognosis remains poor due to the lack of approved second-line therapies to overcome chemoresistance. Genetic analysis revealed frequent mutations in the CDKN2A/ ARF oncosuppressor gene, suggesting a promising therapeutic target and supporting the use of CDK4/6 inhibitors. This study evaluates Myrtleciclib, a novel compound that, unlike traditional CDK4/6 inhibitors, also inhibits CDK9, involved in RNA transcription. MATERIALS AND METHODS: Experiments were performed on a panel of MPM cell lines with different histotypes. Cisplatin- and pemetrexed- resistant clones were obtained by exposing the epithelioid H2452 cell line to increasing drug concentration over six months. In vivo studies were conducted in an immune-competent orthotopic rat recurrence model of MPM. RESULTS: Compared to available CDK4/6 inhibitors, Myrtleciclib showed superior anti-proliferative activity, with IC50 values roughly 50-fold lower across all the MPM cell lines. The inhibition of cell proliferation was associated to a reduced activation of proliferative signalling pathways such as AKT/mTOR and MAPK, and to disruption of the cell cycle progression, as demonstrated by the hypophosphorylation of Rb and reduced c-myc expression. Moreover, Myrtleciclib induced apoptosis by downregulating Mcl-1, a CDK9 target and anti-apoptotic molecule. It also had significant effects on 3D spheroids, causing complete spheroid disruption after 6 days of treatment. Finally, in vivo, treatment prevented tumor relapses compared to controls both locally and in the abdominal cavity. Chemoresistant adaptations constitutes the primary cause of failure of conventional therapies. Hence, the anti-proliferative and pro-apoptotic effects exhibited by Myrtleciclib, even in chemoresistant clones through the induction of caspase 3 cleavage, highlights its potential therapeutic efficacy. CONCLUSION: The frequent CDNKN2A/ARF gene loss in MPM represents a potential therapeutic target, as recently demonstrated by Fennel’s MiST2 clinical trial. Our findings indicate that Myrtleciclib could be a promising and durable second-line therapy for MPM, able to overcome chemoresistance and improve treatment outcomes.
Effects of myrtleciclib, a cyclindependent kinase inhibitor, in models of malignant pleural mesothelioma / 7, 5.F.E., Galetti, M., La Monica, S., Ampollini, L., Alfieri, R., De Forni, D., Poddesu, B., Cugia, G., Cavazzoni, A., Cavallo, D., Lori, F., Petronini, P.G., Bonelli, M.. - (2025), pp. 103-103. (65th Annual Meeting of the Italian Cancer Society. Targeting Cancer Hallmarks ).
Effects of myrtleciclib, a cyclindependent kinase inhibitor, in models of malignant pleural mesothelioma
Galetti M.;La Monica S.;Ampollini L.;Alfieri R.;Cavazzoni A.;Lori F.;Petronini P. G.;Bonelli M.
2025-01-01
Abstract
BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with occupational asbestos exposure, arising from malignant transformation of mesothelial cells in the parietal pleura. For 20 years, chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care; however, prognosis remains poor due to the lack of approved second-line therapies to overcome chemoresistance. Genetic analysis revealed frequent mutations in the CDKN2A/ ARF oncosuppressor gene, suggesting a promising therapeutic target and supporting the use of CDK4/6 inhibitors. This study evaluates Myrtleciclib, a novel compound that, unlike traditional CDK4/6 inhibitors, also inhibits CDK9, involved in RNA transcription. MATERIALS AND METHODS: Experiments were performed on a panel of MPM cell lines with different histotypes. Cisplatin- and pemetrexed- resistant clones were obtained by exposing the epithelioid H2452 cell line to increasing drug concentration over six months. In vivo studies were conducted in an immune-competent orthotopic rat recurrence model of MPM. RESULTS: Compared to available CDK4/6 inhibitors, Myrtleciclib showed superior anti-proliferative activity, with IC50 values roughly 50-fold lower across all the MPM cell lines. The inhibition of cell proliferation was associated to a reduced activation of proliferative signalling pathways such as AKT/mTOR and MAPK, and to disruption of the cell cycle progression, as demonstrated by the hypophosphorylation of Rb and reduced c-myc expression. Moreover, Myrtleciclib induced apoptosis by downregulating Mcl-1, a CDK9 target and anti-apoptotic molecule. It also had significant effects on 3D spheroids, causing complete spheroid disruption after 6 days of treatment. Finally, in vivo, treatment prevented tumor relapses compared to controls both locally and in the abdominal cavity. Chemoresistant adaptations constitutes the primary cause of failure of conventional therapies. Hence, the anti-proliferative and pro-apoptotic effects exhibited by Myrtleciclib, even in chemoresistant clones through the induction of caspase 3 cleavage, highlights its potential therapeutic efficacy. CONCLUSION: The frequent CDNKN2A/ARF gene loss in MPM represents a potential therapeutic target, as recently demonstrated by Fennel’s MiST2 clinical trial. Our findings indicate that Myrtleciclib could be a promising and durable second-line therapy for MPM, able to overcome chemoresistance and improve treatment outcomes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
