Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance
Open Access
- 2 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in npj Precision Oncology
- Vol. 5 (1), 1-13
- https://doi.org/10.1038/s41698-021-00152-9
Abstract
Recurrence of therapy-resistant tumors is a principal problem in solid tumor oncology, particularly in ovarian cancer. Despite common complete responses to first line, platinum-based therapies, most women with ovarian cancer recur, and eventually, nearly all with recurrent disease develop platinum resistance. Likewise, both intrinsic and acquired resistance contribute to the dismal prognosis of pancreatic cancer. Our previous work and that of others has established CLPTM1L (cleft lip and palate transmembrane protein 1-like)/CRR9 (cisplatin resistance related protein 9) as a cytoprotective oncofetal protein that is present on the tumor cell surface. We show that CLPTM1L is broadly overexpressed and accumulated on the plasma membrane of ovarian tumor cells, while weakly or not expressed in normal tissues. High expression of CLPTM1L is associated with poor outcome in ovarian serous adenocarcinoma. Robust re-sensitization of resistant ovarian cancer cells to platinum-based therapy was achieved using human monoclonal biologics inhibiting CLPTM1L in both orthotopic isografts and patient-derived cisplatin resistant xenograft models. Furthermore, we demonstrate that in addition to cell-autonomous cytoprotection by CLPTM1L, extracellular CLPTM1L confers resistance to chemotherapeutic killing in an ectodomain-dependent fashion, and that this intercellular resistance mechanism is inhibited by anti-CLPTM1L biologics. Specifically, exosomal CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines conferred resistance to cisplatin in drug-sensitive parental cell lines. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patients’ serum with increasing abundance upon chemotherapy treatment. These findings have encouraging implications for the use of anti-CLPTM1L targeted biologics in the treatment of therapy-resistant tumors.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (1R01CA229907)
This publication has 42 references indexed in Scilit:
- Down regulation of SPAG9 reduces growth and invasive potential of triple-negative breast cancer cells: possible implications in targeted therapyJournal of Experimental & Clinical Cancer Research, 2013
- The novel cancer-testis antigen A-kinase anchor protein 4 (AKAP4) is a potential target for immunotherapy of ovarian serous carcinomaOncoImmunology, 2013
- A microduplication of 5p15.33 reveals CLPTM1L as a candidate gene for cleft lip and palateEuropean Journal of Medical Genetics, 2013
- CLPTM1L Is Overexpressed in Lung Cancer and Associated with ApoptosisPLOS ONE, 2012
- A Locked, Dimeric CXCL12 Variant Effectively Inhibits Pulmonary Metastasis of CXCR4-Expressing Melanoma Cells Due to Enhanced Serum StabilityMolecular Cancer Therapeutics, 2012
- A Cell Surfaceome Map for Immunophenotyping and Sorting Pluripotent Stem CellsMolecular & Cellular Proteomics, 2012
- Functional Characterization of CLPTM1L as a Lung Cancer Risk Candidate Gene in the 5p15.33 LocusPLOS ONE, 2012
- Bioinformatics construction of the human cell surfaceomeProceedings of the National Academy of Sciences of the United States of America, 2009
- A Novel Gene, CRR9, Which Was Up-Regulated in CDDP-Resistant Ovarian Tumor Cell Line, Was Associated with ApoptosisBiochemical and Biophysical Research Communications, 2001