TRANSLATIONAL CANCER GENETICS

Principal Investigator

Staff

Research topic

Overcoming resistance to therapies exploiting tumor DNA repair and metabolic vulnerabilities.

Background

Therapeutic resistance, either as an intrinsic (primary) feature or as an acquired (secondary) trait upon the exposure to targeted or chemotherapeutic agents, represents the major cause of treatment failure in cancer patients. The identification of culprits of resistance or, on the other side, of determinants of sensitivity to therapy denotes an unmet medical need for the design of novel strategies to overcome resistance and to prolong disease control in cancer patients. Over the past two decades, advances in tumor biology and genomic profiling have established precision medicine as a paradigm for guiding cancer care. However, to extend therapeutic benefit to the substantial proportion of patients who do not respond to currently actionable alterations, genomic profiling should now be integrated with more comprehensive non-genetic approaches. Colorectal, prostate, and ovarian cancers rank among the most prevalent and lethal solid malignancies worldwide (Siegel RL et al, CA Cancer J Clin. 2025). Although these tissues are heterogeneous and different for embryonic origins and functions, common mechanisms of survival might be exploited and targeted to lethally impair tumor growth and progression. 

Research achievements

Previous work has led to the discovery of genetic mechanisms of acquired resistance to anti-EGFR therapy in colorectal cancer (CRC), in particular to the identification of mutations in the EGFR pathway (Misale*, Arena* et al. Sci Transl Med 2014) and in the EGFR extracellular domain (ECD) (Arena et al, Clin Cancer Res 2015; Arena et al., Sci Transl Med 2016). By modelling evolution of resistance in vitro upon drug pressure, we have also shown that a correlation can occur between the genetic profile of the patients and their clinical outcome, thereby underscoring the profound impact of intratumoral heterogeneity on therapeutic response (Van Emburgh*, Arena* et al., Nature Comm 2016). While most common therapeutic approaches might adapt to the ‘resistant genetic profile’ of the patient (Arena et al., Sci Trasl Med 2016), we have recently devised novel strategies that take advantage of intrinsic or acquired vulnerabilities independent from the EGFR axis. These include both metabolic susceptibilities (Lorenzato, and Arena, Cancers 2020; Alaimo et al., Mol Oncol 2025; Richiardone et al, Cancer Lett. 2025) and dependencies on DNA damage repair pathways (Arena et al., Clin Cancer Res 2020; Durinikova et al., Clin Cancer Res 2022, Corti et al, NPJ Precis Oncol.2024). These liabilities might embody putative and effective druggable targets for cancer treatment. In addition, establishment of preclinical platforms of patient-derived models that faithfully recapitulate the molecular complexity and heterogeneous clinicopathological features of the disease (Lazzari et al., Clin Cancer Res 2019; Durinikova et al., J Exp Clin Cancer Res. 2021, Mauri*, Durinikova* et al, JCO Precis Oncol. 2021, De Lazzari et al., J Exp Clin Cancer Res. 2024) enables successful translational application of these strategies, further supporting their potential for improving patient treatment outcomes.

Conclusions and perspectives

The Laboratory of Translational Cancer Genetics is currently focused on the development of novel therapeutic strategies aimed at overcoming heterogeneous resistance in colorectal, prostate, and ovarian cancers. This objective is pursued through the rational combination of standard targeted or chemotherapeutic agents with the unconventional and concomitant inhibition of collateral cellular vulnerabilities. Development of cancer therapies based on synthetic lethal targeting of the DNA damage response (DDR) and metabolic pathways might provide an opportunity for the design of novel drug combinations to elicit synergistic activity with tolerable toxicities and foster the long-term response to therapies. Translational relevance is ensured by evaluating therapeutic efficacy in patient-derived preclinical models, including cell lines, organoids (PDOs), and patient-derived xenografts (PDXs), that faithfully reproduce the molecular and clinical complexity of these malignancies.

Publications

At this link, you can find all the scientific publications of the Principal Investigator.