Improvement and extension of anti-EGFR targeting in breast cancer therapy by integration with the Avidin-Nucleic-Acid-Nano-Assemblies

Abstract

Nowadays, personalized cancer therapy relies on small molecules, monoclonal antibodies, or antibody–drug conjugates (ADC). Many nanoparticle (NP)-based drug delivery systems are also actively investigated, but their advantage over ADCs has not been demonstrated yet. Here, using the Avidin-Nucleic-Acid-Nano-Assemblies (ANANAS), a class of polyavidins multifuctionalizable with stoichiometric control, we compare quantitatively anti-EGFR antibody(cetuximab)-targeted NPs to the corresponding ADC. We show that ANANAS tethering of cetuximab promotes a more efficient EGFR-dependent vesicle-mediated internalization. Cetuximab-guided ANANAS carrying doxorubicin are more cytotoxic in vitro and much more potent in vivo than the corresponding ADC, leading to 43% tumor reduction at low drug dosage (0.56 mg/kg). Advantage of cetuximab-guided ANANAS with respect to the ADC goes beyond the increase in drug-to-antibody ratio. Even if further studies are needed, we propose that NP tethering could expand application of the anti-EGFR antibody to a wider number of cancer patients including the KRAS-mutated ones, currently suffering from poor prognosis.

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

“…and K32 in which the metastatic lesions contained FGFR and EGFR ampli cations [36,37]. Case K30 and K32, which had decreased ATM might be sensitive to topotecan or the poly-(ADP-ribose) polymerase inhibitor olaparib [38].…”

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

“…Case K18 and K28 (triple-negative cancers) with CCND1 gene amplification might be sensitive to CDK4/6 inhibitors [36]. Meanwhile, erdafitinib and cetuximab might be effective for cases K30 and K32 in which the metastatic lesions contained FGFR and EGFR amplifications [37,38]. Case K30 and K32, which had decreased ATM might be sensitive to topotecan or the poly-(ADP-ribose) polymerase inhibitor olaparib [39].…”

Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

“…Case K18 and K28 (triple-negative cancers) with CCND1 gene ampli cation might be sensitive to CDK4/6 inhibitors [35]. Meanwhile, erda tinib and cetuximab might be effective for cases K30 and K32 in which the metastatic lesions contained FGFR and EGFR ampli cations [36,37]. Case K30 and K32, which had decreased ATM might be sensitive to topotecan or the poly-(ADP-ribose) polymerase inhibitor olaparib [38].…”