Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance

摘要: Recurrence of therapy-resistant tumors is a principal problem in solid tumor oncology, particularly ovarian cancer. Despite common complete responses to first line, platinum-based therapies, most women with cancer recur, and eventually, nearly all recurrent disease develop platinum resistance. Likewise, both intrinsic acquired resistance contribute the dismal prognosis pancreatic Our previous work that others has established CLPTM1L (cleft lip palate transmembrane protein 1-like)/CRR9 (cisplatin related 9) as cytoprotective oncofetal present on cell surface. We show broadly overexpressed accumulated plasma membrane cells, while weakly or not expressed normal tissues. High expression associated poor outcome serous adenocarcinoma. Robust re-sensitization resistant cells therapy was achieved using human monoclonal biologics inhibiting orthotopic isografts patient-derived cisplatin xenograft models. Furthermore, we demonstrate addition cell-autonomous cytoprotection by CLPTM1L, extracellular confers chemotherapeutic killing an ectodomain-dependent fashion, this intercellular mechanism inhibited anti-CLPTM1L biologics. Specifically, exosomal from cisplatin-resistant carcinoma lines conferred drug-sensitive parental lines. vesicle fractions culture supernatants patients' serum increasing abundance upon chemotherapy treatment. These findings have encouraging implications for use targeted treatment tumors.