Tumor Heterogeneity and Resistance to Cancer Therapies

The sequences of cancer genomes and the development of oncogene-specific inhibitors have transformed the clinical treatment of cancer patients into what is commonly known as precision or personalized medicine.

However, it is widely known that each tumor contains a “private” collection of molecular alterations, few of which are shared between patients with the same histopathological subtype. Additionally, intrapatient heterogeneity also exists not only between the primary tumor and metastatic lesions but also between separated regions of the same tumor lesion, in which the coexistence of genetically distinct clonal subpopulations is often observed.

Such a high level of intratumor heterogeneity, indicating branched rather than linear tumor evolution, profoundly affects the efficacy of cancer therapy. When therapies are administered, lesion-specific responses can be observed with resistant subclones, eventually leading to disease progression.

Furthermore, there is clear evidence that therapy reshapes the tumor mutational landscape. Most cancers that initially respond to treatment eventually relapse, with the outgrowth of cancer cells that are genetically and epigenetically different from those that were present at the time of diagnosis.

The critical role of molecular heterogeneity and clonal evolution in the clinical outcomes of cancer patients leads to many clinical and scientific needs:

-Clinical trials, novel technologies, and biomarker studies providing accurate molecular maps of individual tumors and longitudinal analyses of tumor evolution during therapeutic treatment.

- Preclinical models of each patient’s specific disease, allowing for rapid development of the most effective personalized therapy.

- The identification of common (trunk) cell vulnerabilities suitable for therapeutic targeting.

- Innovative therapeutic strategies able to overcome the challenges posed by tumor heterogeneity and to prevent clonal evolution.