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.
Highlights
Nine of ten ovarian cancer patients succumb to recurrent, chemoresistant disease, presenting a dire unmet need
We have previously shown that inhibition of CLPTM1L can chemosensitize pancreatic ductal adenocarcinoma to gemcitabine treatment[10,11,12]
We investigated copy number variation (CNV) of various cancer cell lines using the depmap portal and found that ovarian cancer (n = 51) is among several tumor cell lines with high CNV of CLPTM1L compared to fibroblasts (n = 36) (Fig. 1d)
Summary
Nine of ten ovarian cancer patients succumb to recurrent, chemoresistant disease, presenting a dire unmet need. In pancreatic cancer a challenging tumor microenvironment and unknown factors contribute to a strong resistance to therapy. We have recently identified surface-expressed CLPTM1L to be a tumor-specific cytoprotective and chemoresistance factor in pancreatic and other tumor types that can be further induced by genotoxic or endoplasmic reticular stress[2,10,11,12]. Several other studies have demonstrated robust overexpression of CLPTM1L on the surface of malignant cells in a variety of tumor types with minimal nonsurface expression or no expression in normal tissues[2,10,11,12,14,15,16,17]
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