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Repair of DNA lesions induced by platinum drugs

Periodic Reporting for period 1 - REAP (Repair of DNA lesions induced by platinum drugs)

Reporting period: 2019-05-01 to 2021-04-30

The aim of the REAP 843630 was to understand the molecular principles underlying the tumor’s differential treatment response to platinum drugs and to identify novel predictive and prognostic markers.
In gastrointestinal cancers, unlike in any other type of solid tumors, the responsiveness to oxaliplatin is superior to cisplatin. Hence, colon cancer is one of the few cancer types exclusively treated with oxaliplatin. Still, the sensitivity of colon tumors to this platinum drug varies between patients. The specificity of oxaliplatin for gastrointestinal cancers was not mechanistically explained to date and there were no clinical markers identified to pre-select oxaliplatin-susceptible patients to achieve the best treatment results. In order to address these points, we set to comprehensively explore the cellular processes that recognize and remove oxaliplatin and cisplatin-DNA lesions. Generation of DNA damage is the main mechanism of platinum drugs leading to tumor inhibition and DNA repair processes modulate the tumor response. We, therefore, hypothesized that cancer-specific differences in the repair of these lesions could explain distinct clinical efficiencies of platinum drugs.
We observed that a subset of colon tumors is deficient in removing oxaliplatin-DNA lesions by one of the main DNA repair pathways, global-genome nucleotide excision repair (GG-NER). This pathway is represented by the rate-limiting activity of XPC protein. Based on this observation, we formulated three main objectives: Objective 1: Identify factors determining diverse XPC behavior on oxaliplatin versus cisplatin lesions. Objective 2: Identify the molecular mechanism of XPC regulation in oxaliplatin and cisplatin lesions recognition, and Objective 3: Identify DNA repair molecular signature in cancer patients’ tumors, related to treatment response to oxaliplatin.
All the objectives and deliverables were achieved within the project period covered by this final report. Our main observations are:
a. The mechanism of cisplatin and oxaliplatin-DNA lesions recognition differs, and we described a novel mechanism responsible for the repair of oxaliplatin-DNA lesions (Image1).
b. Cisplatin-DNA lesions represent a strong substrate for GG-NER and XPC itself is sufficient to trigger the GG-NER repair after recognizing the lesions.
c. Oxaliplatin-DNA lesions represent poor GG-NER substrate, and their recognition requires at least 3 different factors and additional post-translational modifications.
d. Proteins required for oxaliplatin-DNA lesions recognition are DDB2 and HMGA2 (protein never described to be involved in NER process before) that stimulate XPC affinity to DNA lesions and that leads to initiation of repair.
e. SUMOylation of some of the above factors is required via UBA2 (also never described before to be involved in the NER process).
f. Around 50% of colon cancer cells are lacking the capacity to recognize oxaliplatin-DNA lesions by GG-NER, due to low levels of DDB2 and HMGA2, explaining thus their higher clinical sensitivity to oxaliplatin over cisplatin (Image2).
g. DDB2 expression levels are strongly associated with the overall survival of colon cancer patients treated with oxaliplatin.
h. Low DDB2 levels predict better survival (in compliance with our ex vivo data, showing low DDB2 associated with low GG-NER leading thus to higher oxaliplatin sensitivity).
i. DDB2 association with clinical outcome is very specific to oxaliplatin and not seen in patients treated with cisplatin (in compliance with our ex vivo data, showing that DDB2 is not involved in cisplatin repair).
j. We identified DDB2 as a novel promising predictive/prognostic marker for oxaliplatin-treated colon cancer (Image2).
Spanning the duration of the project covered by the final report, we succeeded to identify the protein, expression levels of which are tightly associated with the treatment response of colon cancer patients to oxaliplatin-based treatment regimens. We described the involvement of this protein in the cellular response to oxaliplatin-DNA lesions and we validated its role in treatment response using patient-derived samples. In the following steps, we plan to validate this marker further on an independent set of colon tumors.
At the final stage of the project, we identified novel factors, DDB2 and HMGA2, involved in the clearance of oxaliplatin-DNA lesions. We believe that their targeted inhibition in combination with oxaliplatin treatment will greatly increase the success rate in colon cancer treatment outcomes. Therefore, this new combinatorial therapy will be tested beyond the final report.
Lastly, we plan to explore the precise mechanism of platinum-DNA lesions by GG-NER. We will divide the group of platinum-induced DNA lesions into subcategories of different intra- and inter-strand crosslinks and describe the requirement for different repair factors of the DNA repair machinery. Detail understanding of the repair processes of these clinically relevant drugs brings us a step further to their therapeutical utilization.
Figure 1: A distinct resolution of cisplatin and oxaliplatin-DNA crosslinks by GG-NER
Figure 2: Deficiency of colon cancer in oxaliplatin-DNA lesions repair increases treatment response