Abstract 473P
Background
Polo-like Kinase 1 (PLK1) is a serine/threonine protein kinase that has emerged as a next generation antimitotic target in cancer therapy, with several PLK inhibitors in development. PLK1 is highly expressed in many cancers and is associated with poor prognosis. Oncogenic mutations in the GTPase protein KRAS are prevalent (35-40%) in colorectal cancer (CRC) and are associated with resistance to targeted therapies. KRAS-mutant (MT) cells are particularly dependent on genes implicated in mitotic functions, such as PLK1.
Methods
We retrospectively reviewed 4551 CRC tumors profiled with Caris Life Sciences from 2019 to 2020. Profiling included whole transcriptome sequencing, targeted next-generation sequencing, tumor mutational burden (TMB), deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) status, and immunohistochemistry. The Microenvironment Cell Populations (MCP)-counter method was used to assess immune infiltration the tumor microenvironment.
Results
Median PLK1 expression was similar in KRAS-MT vs KRAS-WT tumors (29.1 vs 31.2 transcripts per million [TPM]; p=0.043). Metastases had significantly lower PLK1 expression compared to primary tumors (26.6 vs 32.9 TPM; p<0.001). Tumors in the top quartile (Q4) PLK1 expression group were more frequently associated with a rectal primary site compared to the bottom quartile (Q1) group (27.3 % vs 17.7%; p<0.001). Q4 tumors had increased mutation rates of TP53 (81.3% vs 68.1%), APC (78.7% vs 66.9%), and MSH6 (4.0% vs 1.3%) compared to Q1 (p<0.001). dMMR/MSI-H (8.6% vs 2.7%) and TMB (8.8% vs 2.9%) were also significantly increased in Q4 compared to Q1 (p<0.001). Relative immune cell population abundance and checkpoint gene expression increased gradually from Q1 to Q4 (p<0.001).
Conclusions
A lack of increased PLK1 expression suggests similar potential for PLK1 inhibitors in KRAS-MT tumors compared to KRAS-WT. Among PLK1 expression groups, proportionate increases in dMMR/MSI-H, TMB, immune cell populations, and immune checkpoint gene expression suggest a potential response to immunotherapy in tumors with increased PLK1 expression. Combining immunotherapy with a PLK1 inhibitor might be a synergistic approach to increase sensitivity in PLK1-overexpressing CRC regardless of KRAS status.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
USC.
Funding
Has not received any funding.
Disclosure
E. Lou: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novocure; Honoraria (self), Travel/Accommodation/Expenses: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy: Boston Scientific. W.M. Korn: Leadership role, Full/Part-time employment: Caris Life Sciences; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Sharp and Dohme. All other authors have declared no conflicts of interest.