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Predicting resistance to anticancer drugs

2021-06-17
(Press-News.org) Cancer cells can develop resistance to therapy through both genetic and non-genetic mechanisms. But it is unclear how and why one of these routes to resistance prevails. Understanding this 'choice' by the cancer cells may help us devise better therapeutic strategies. Now, the team of Prof. Jean-Christophe Marine (VIB-KU Leuven Center for Cancer Biology) shows that the presence of certain stem cells correlates with the development of nongenetic resistance mechanisms. Their study is published in the prestigious journal Cancer Cell. Two routes to resistance Even though cancer therapy has made great strides in the last few years, resistance remains a major problem. When cancer cells develop resistance against the drugs targeting them, they can continue to spread, even when the patient is going through therapy.

Until recently, it was thought that this resistance arises exclusively through mutations - genetic alterations - in the cancer cells. However, new studies have suggested that resistance against cancer drugs can also arise via non-genetic mechanisms that change the expression of certain genes without altering the DNA sequence.

Prof. Jean-Christophe Marine (VIB-KU Leuven Center for Cancer Biology): "The importance of nongenetic reprogramming as a driver of therapy resistance is not yet widely accepted in the field. Although my group has demonstrated that drug tolerance can be driven by nongenetic mechanisms, strong evidence that resistance can be acquired in absence of a genetic cause is still lacking."

In their study, the team of Prof. Marine firmly establishes that nongenetic mechanisms contribute to resistance to therapy in melanoma. The key question has become: "How do cancer cells 'choose' between the different routes to resistance?"

Neural crest stem cells as key Surprisingly, the team demonstrates that the road to resistance is predetermined and not randomly selected. They show that the presence of a specific group of cells, neural crest stem cells, leads to non-genetic rather than genetic drug resistance in melanoma. A possible reason for this is that these neural crest stem cells exhibit 'epigenetic plasticity', which means that these cells have an increased ability to select which genes they express and how much. These cells literally reprogram themselves to evade the therapeutic pressure.

The researchers also identified the signaling pathway that drives the emergence of the neural crest stem cells and promotes their survival. This signaling pathway depends crucially on the protein Focal Adhesion Kinase (or FAK). By blocking the activity of this protein, the team was able to drastically reduce the occurrence of non-genetic drug resistance in patient-derived xenografts - tumor cells from human patients that were implanted in mice.

This combination of new basic insights into tumor cell biology and recently discovered non-genetic resistance mechanisms to cancer drugs has far-reaching clinical consequences.

Florian Rambow, senior postdoc who contributed to the study, explains: "These findings have several important clinical implications. Not only did we show a viable way to suppress non-genetic resistance, but we also demonstrated that the presence of specific cells dictates which resistance mechanism is likely to occur. This observation is the key to predicting potential resistance routes in patients and developing personalized therapies."

INFORMATION:

Publication Marin-Bejar et al. (2021). Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer Cell.

Financing The KULeuven PDX platform is supported by the Stichting Tegen Kanker grant 2016-054. E.L. is supported by the Melanoma Research Alliance (MRA) Amanda and Jonathan Eilian young investigator award. O.M-B. is supported by 12T1217N project by FWO at the program under the Marie Sk?odowska-Curie grant agreement no. 665501. P.K. received financial support from Marie Curie Individual Fellowship (H2020?MSCA?IF?2018), J.P. received financial support from Marie Curie Individual Fellowship (H2020-MSCA-IF-2019), and J.F. from the Swedish Research Council (Vetenskapsrådet, International postdoc grant, Reg.-Nr.: 2016-00215). J.D. is supported by a postdoctoral fellowship from FWO (12J6921N). D.P. and N.V.R. received PhD fellowships from the VIB PhD international program and FWO-SB 1S79619N, respectively. This work was supported by FWO (#G.0929.16N), Stichting tegen kanker, Interreg (Skin-Huid), Melanoma Research Alliance (MRA, EIA#623591), KULeuven (C1 grant #C16/19/006) to J-C.M., an OHSU Knight Cancer Center support grant from the National Institutes of Health (NIH P30-CA069533) to A.W.L., Infrastructure grants (type 1 funding from the Hercules Foundation - AKUL/13/41; Foundation Against Cancer project 2015-143) and grants from FWO (I001818N) and KU Leuven C14/18/092 to T.V. and enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (grant number MR/L016311/1).

Questions from patients A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: patienteninfo@vib.be. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.



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[Press-News.org] Predicting resistance to anticancer drugs