Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer

Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos

“…A recent study has revealed that metastatic therapy-resistant prostate cancer cells undergo transcriptional reprogramming to adapt to persistently elevated CIN by upregulating mitotic fidelity pathways which restrain accumulation of lethal levels of chromosomal errors. This study emphasizes the role of cell rewiring at the chromatin level as a potentially relevant mechanism for adapting to ongoing CIN in metastatic therapy-refractory tumors, and shows that targeting this axis is a feasible strategy to selectively target them by exacerbating their chromosome missegregation rate over the tolerable threshold (Dhital et al 2023 ). This concept of upregulation of genome integrity pathways’ to tune down excessive levels of chromosomal abnormalities, which would compromise cell fitness and proliferation, is gaining more momentum.…”

“…In this regard, the initial clinical correlations indicating CIN to be higher in highly aggressive tumors have been confirmed in pan-cancer genome sequencing studies using FGA as a proxy, as well as using gene signatures and analysis of tissue samples to score missegregation events in anaphases (Bakhoum et al 2018 ; Carter et al 2006 ; Dhital et al 2023 ; Drews et al 2022 ; Miller et al 2020 ; Nguyen et al 2022 ). All these studies indicate that CIN is higher in metastatic disease stages and is particularly enriched in specific tumor types.…”

“…All these observations in normal and tumors tissues have helped to better contextualize the well-known CIN and aneuploidy paradox, that postulates that CIN can be both detrimental and advantageous and conclude that CIN-persistent cells existing in tumors can themselves be susceptible to excessively high levels of chromosomal aberrations. Further supporting this idea, a recent study has demonstrated that high-CIN therapy-refractory metastatic tumors develop transcriptionally driven vulnerabilities that can be targeted to induce lethal levels of chromosomal aberrations in tumors (Dhital et al 2023 ).…”

“…The future of the CIN field should address these questions at the molecular level in experimental models and using clinical patient data. Despite the significant preference for CIN accumulation in cancer cells, the actual rates of CIN in human cancer are just starting to be comprehensibly studied at the genomic level in patients, indicating a clear correlation between higher CIN levels and metastases (Dhital et al 2023 ; Drews et al 2022 ; Nguyen et al 2022 ). It will be paramount for future studies to be able to match clinical findings to molecular mechanisms of CIN induction and modulation using experimental approaches in different tumor cell models.…”

“…Similarly, another example of therapeutically targeting cell cycle essential genes in the context of specific functional vulnerabilities of cancer cells identified a specific dependency on CCNE1 (cyclin E) upregulation/amplification in tumor cells, which can be selectively targeted using inhibitors of PKMYT1 (a. k. a Myt1), an essential mitotic kinase (Gallo et al 2022 ). Finally, recent studies on metastatic prostate cancer have also proposed targeting high-CIN therapy-refractory tumors, elevating tumor chromosomal aberration to lethal levels by inhibiting the mitotic fidelity kinase MASTL (Dhital et al 2023 ). These two abovementioned studies suggest that the upregulation of the cell cycle and mitotic machinery observed in certain tumors may not just only be a cause of initial CIN generation or pure proliferation; but at least in the case of advanced aggressive tumors already sufficiently replete with CIN, the mitotic fidelity mechanisms may have adapted to be more efficient creating new strong dependencies and unique vulnerabilities that can be therapeutically exploited in cancer cells.…”