Translational Cancer Genetics
Sabrina Arena, Ph.D.
Associate Professor University of Torino, School of Medicine
Overcoming resistance to therapies exploiting tumor DNA repair and metabolic vulnerabilities
Therapeutic resistance, either as an intrinsic (primary) feature or as an acquired (secondary) trait upon the use of 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. Thanks to increased knowledge in tumor biology, genomic profiling, that has driven in the last two decades the primary precision medicine strategy to guide patient care, should be now coupled to more complex non-genetic profiling to extend therapeutic benefit also to that large part of patients that are not responding to common actionable targets. Tumors of colorectal, prostate and ovarian origin are among the top five solid malignancies affecting cancer patients worldwide (Siegel et al, cancer Statistics 2022). 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.
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 clinical correlation can occur between the genetic profile of the patients and their clinical outcome, thus highlighting the profound implications of tumor heterogeneity on therapy (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 susceptibilities independent from the EGFR axis and standing from metabolic vulnerabilities (Lorenzato, and Arena, Cancers 2020) to DNA repair pathway dependencies (Arena et al, Clin Cancer Res 2020; Durinikova et al, Clin Cancer Res 2022). These liabilities might embody putative and effective druggable targets for cancer treatment. In addition, establishment of preclinical platforms of patient-derived models that faithfully mirror the molecular and heterogeneous clinical-pathological 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) has shown successful translational application of these therapeutic strategies to treat cancer patients.
Conclusions and perspectives:
The laboratory of Translational Cancer Genetics is currently focused on the design of novel therapeutic strategies to overcome heterogeneous resistance in cancers of colorectal, prostate and ovarian origin. This could be achieved by exploiting the combination of common targeted or chemotherapeutic agents with the unconventional and concomitant targeting of collateral cell 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 application is provided by testing efficacy in patient-derived preclinical models (cell lines and organoids, PDXs) that faithfully recapitulate the clinical settings of these tumors.
Kristi Buzo, Dr
Clelia Nisticò, Dr
Laura Bizzozero, Dr
Giada De Lazzari, Dr
Dr. Alena Opattova, Dr