New approach to identify molecular targets for improved prostate cancer therapy

In a new study, researchers have introduced Differential Subclone Eradication and Resistance Analysis (DSER), a technique for identifying molecular targets for enhanced therapy in prostate cancer.

Image Credit: University of Eastern Finland.

The study titled “Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity” was headed by Academy Research Fellow Kirsi Ketola from the Institute of Biomedicine and UEF CANCER Research Community, University of Eastern Finland, and Professor Steven Bova from Tampere University.

The DSER technique involves performing a direct comparison of genomic features of resistant and eradicated cancer cells in pre-and post-treatment samples obtained from a patient. The researchers used a single patient with metastatic prostate cancer, “A34,” to exhibit the utility and potential of the DSER technique.

Professor Bova and his colleagues earlier studied patient A34 in their study published in Nature Communications in 2020 (Woodcock et al.) and is the first evidenced case of cancer cell eradication because of treatment in a solid tumor.

Performing DSER in case A34 led us to discover changes in the DNA repair genes FANCI and EYA4 in his eradicated cancer cells that may have sensitized them to chemotherapy. In the future, using drugs targeting genes identified using DSER could help ensure that all cancer cells in a patient remain susceptible to therapy.”

Steven Bova, Professor, Tampere University

EYA4, one of the genes determined using DSER, was linked with an adjacent LINE-1 (L1) transposon insertion during the cancer evolution of A34, raising doubts related to the role of therapy in L1 activation.

The researchers employed prostate cancer cell lines to analyze whether androgen-deprivation and chemotherapy treatments could have activated L1s and thus contributed to the eradication or resistance of cancer cells to treatment.

We were fascinated to find that both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC-3 and 22Rv1 prostate cancer cell lines. The L1 activation in LNCaP and VCaP could be further inhibited by the antiretroviral drug azidothymidine, which tells us that existing drugs can be used to manipulate L1 activity in vitro.”

Kirsi Ketola, Academy Research Fellow, Institute of Biomedicine and UEF CANCER Research Community, University of Eastern Finland

Moreover, the team also discovered evidence of L1 activation in other tumor samples, for example, in post-castration patient-derived xenograft models and in post-chemotherapy head and neck cancer cells. This indicates that L1 activation after treatment extends to clinical patient samples. However, more studies are required to determine to what extent this is the case.

The study shows that the DSER technique offers an informative intermediate step toward effective precision cancer medicine and should be investigated in future studies, specifically those including drastic yet temporary metastatic tumor regression.

L1 transposon activation could serve as a modifiable cancer genomic heterogeneity source, indicating the potential of exploiting newly discovered triggers and blockers of L1 activity to handle therapy resistance.