Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells
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ABSTRACT:
SUBMITTER: Prof. Steffen Boettcher
PROVIDER: S-SCDT-10_1038-S44321-024-00024-2 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cell therapy might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are unable to control AML cell outgrowth in vitro and in vivo compared to TP53 wildtype cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.
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Project description:Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. IMPLICATIONS: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.
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Project description:Despite effective strategies, therapy resistance in HER2+ breast cancer remains a challenge. While the Mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Using HER2+ breast cancer parental (P) cell models (AU565, SKBR3, and UACC812), we have established anti-HER2-resistant derivatives made resistant to lapatinib (LR) or lapatinib plus trastuzumab (LTR). We performed RNA-seq on these resistant models and the P cells treated with lapatinib or lapatinib plus trastuzumaba for 24 h. We found that the average expression of the key genes in the MVA pathway, as a surrogate for pathway activity, was dramatically reduced in P cells with short-term treatment. In contrast, expression was restored or further upregulated relative to P cells in all three resistant (LR/LTR) models. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the n-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of resistant cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), but not by cholesterol. Activated YAP/TAZ and mTORC1 signaling and their downstream target gene product Survivin were inhibited by MVA blockade especially in the LR/LTR models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated S6 levels despite blockade of the MVA. The MVA may provide alternative signaling leading to cell survival and resistance when HER2 is blocked by activating YAP/TAZ-mTORC1-Survivin signaling suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy and warrant further clinical investigation.
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