Colorectal cancer (CRC) is the third leading cause of death in the world. CRC shows variable phenotypic make-ups; among them, a particularly aggressive histological subtype is the “high grade mucinous” (HGM) adenocarcinoma, highly mucinous, prone to metastasis and typically refractory to treatments. In some cases, HGM is accompanied by a peculiar “signet ring” phenotype of cancer cells. Early stage diagnosis of signet ring HGM is rare, clinical symptoms occur late and most cases are detected at an advanced stage, with a poor overall survival. We demonstrated that a transcriptional signature of HGM displays negative prognosis and sensitivity to the NEDD-8 inhibitor pevonedistat, suggesting the involvement of neddylation- and ubiquitination-based mechanisms in these cases.
To assess the clinical potential of HGM identification and targeting by pevonedistat or other inhibitor of proteasome pathway, we recently propagated cells and PDXs from a case of early onset, metastatic CRC in a Lynch syndrome patient, refractory to standard care (FOLFOX6, FOLFIRI-Panitumumab) and, surprisingly, also to nivolumab. The tumor was highly mucinous, with signet ring undifferentiated cells.
Mutational analysis on tumor tissue highlighted PIK3CA H1047R mutation and no mutations in KRAS, NRAS or BRAF. Surprisingly, exome analysis on two lesions from a subsequent surgery displayed a different scenario: KRAS G13D but not PIK3CA mutation. Probably these discording results suggest a strong tumor heterogeneity and evolution. Considering the failure of all previous therapies, the lack of actionable genetic alterations and the peculiarity of the phenotypic features, PDX models (organoids and 2D cell cultures) were derived from the two latter lesions and tested for sensitivity to the NEDD8 pathway inhibitor pevonedistat and the proteasome inhibitor bortezomib. Interestingly, all models showed a strong sensitivity to both drugs, in particular to bortezomib.
This is an example of a rare case of HGM colorectal cancer where the integration of several approaches proves useful to identify possible therapeutic strategies for a patient without further standard treatment options.
Candiolo Cancer Institute, FPO-IRCCS
AIRC, FPRC- Ministero della Salute 5X1000 2011
All authors have declared no conflicts of interest.