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NF1 modulates microtubular repair and dictates sensitivity to maytansinoid antibody-drug conjugates in HER2-positive breast cancer

ABSTRACT: NF1 modulates microtubular repair and dictates sensitivity to maytansinoid antibody-drug conjugates in HER2-positive breast cancer

PROVIDER: PRJNA1113536 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29082245_1.fastq.gz	Fastqsanger.gz
	SRR29082245_2.fastq.gz	Fastqsanger.gz
	SRR29082246_1.fastq.gz	Fastqsanger.gz
	SRR29082246_2.fastq.gz	Fastqsanger.gz
	SRR29082247_1.fastq.gz	Fastqsanger.gz

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NF1 modulates microtubular repair and dictates sensitivity to maytansinoid antibody-drug conjugates in HER2-positive breast cancer

Project description:NF1 is a tumor suppressor widely mutated across several cancers. Its best characterized function is the inhibition of RAS signaling through its GTPase-Activating Protein (GAP) domain. Additional functions have been proposed but not deeply investigated, due to its large size and complex domain structure. Here, combining patient data, in vitro/in vivo models and protein biochemistry, we show that NF1 is a novel Microtubule-Associated Protein (MAP) that modulates microtubular dynamics and intra-tubular repair. NF1 loss results in mitotic defects such as prolonged mitosis, supranumerary centrosomes and chromosome missegregation, leading to low-grade aneuploidy in cell lines and patients. Loss of NF1-mediated intratubular repair creates a liability specifically targetable by maytansinoids, a class of microtubule-depolymerizing agents widely used as payloads in Antibody-Drug Conjugates such as Trastuzumab-Emtansine (T-DM1). Our results directly imply loss of intratubular repair as a driver of tumorigenesis, and NF1 as the first ADC payload-associated biomarker.

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SNX10 deficiency confers resistance to anti-HER2 antibody-drug conjugates via regulating endosomal trafficking

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Immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity II

Project description:Innate pattern recognition receptors, including toll-like receptors (TLRs), can alter the tumor microenvironment and prime adaptive anti-tumor immunity. However, TLR agonists have not been well-tolerated due to toxicities associated with widespread immune activation following systemic administration. To design a therapeutic that is suitable for systemic delivery and capable of eliciting a tumor-targeted response, we developed a novel class of immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 agonist conjugated to tumor-targeting antibodies. Systemically administered anti-HER2 ISACs were well-tolerated in vivo and elicited robust activation of intratumoral myeloid cells, resulting in tumor clearance and subsequent immunological memory. In vitro potency and in vivo efficacy required tandem activity driven by intact Fc functionality and TLR agonism to enable phagocytosis and T cell-mediated anti-tumor immunity. ISAC-mediated immunological memory was not limited to HER2, as ISAC-treated mice were protected from rechallenge with a HER2-negative tumor. These results provide strong rationale for the clinical development of ISACs and show that synergy between FcgR and TLR7/8 signaling contributes to the mechanism of ISAC-mediated anti-tumor immunity.

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