New insights from the widening homogeneity perspective to target intratumor heterogeneity

Abstract

Precision medicine has shed new light on the treatment of heterogeneous cancer patients. However, intratumor heterogeneity strongly constrains the clinical benefit of precision medicine. Thus, rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions, but also provide an avenue for precision medicine. Here, we explore the current approaches for targeting intratumor heterogeneity and their limitations. Furthermore, we propose a theoretical strategy with a "homogenization" feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.

Keywords: Acquired drug resistance; Homogenization; Intratumor heterogeneity; Plasticity; Precision medicine.

Fig. 1

Current strategies targeting intratumor heterogeneity. Four strategies to solve this problem are as follows. First, targeting a shared pathway. Second, targeting the primary mutation together with the anticipated mutation. Third, finding a target controlling intratumor heterogeneity and plasticity. Fourth, epigenetic therapy that primes cancer to restore sensitivity

Fig. 2

Driver mutations in tumor evolution. A cell develops a specific driver mutation that gives rise to a benign tumor. The cell then develops an additional driver mutation to invade surrounding tissues. Subsequently, the cell develops an additional driver mutation that enables the tumor to engage in hematogenous metastasis. Thereafter, the tumor may acquire additional driver mutations to propagate and sustain intratumor heterogeneity

Fig. 3

Schematic depiction of “homogenization” therapy. First, a homogeneous cell population is induced, followed by administration of a drug to which the cells are sensitive to eradicate the tumor population