Figure 6.

Resistance to cancer therapies, clonal selection, and cancer cell survival: Cancer treatment can involve either a single therapy or combination of surgery, targeted therapies, radiotherapy, broad spectrum chemotherapeutics, immune-therapeutics, hormonal therapy, personalized therapy, bone marrow transplants, and complementary and alternative medicine. Malignant cells display resistance to treatments through a myriad of genetic and non-genetic mechanisms. The loss of function of tumor-suppressor genes and the gain of function of proto-oncogenes provides a survival advantage to cancer cells. Various selective pressures from scarcity for nutrients, and oxygen, treatment modalities, patient lifestyle factors, and body tissue environments can help certain cancer cells gain features (i.e., clonal selection) that support survival and advance disease progression. The ability to adapt allows cancer cells ability to survive during any stage of the disease progression. Therapeutic resistance may occur at the time of initial therapy (i.e., primary resistance) or post therapy (i.e., acquired resistance). Primary resistance may result from intrinsic and/or adaptive resistance owing to ineffective targeting of the oncogenic drivers and/or rapid rewiring of oncogenic signaling after the initial suppression or may be due to non-therapy related selective pressures. Due to heterogeneity within a tumor mass, tumors can harbor rare subclones with treatment resistance mechanisms even before the initiation of therapy. Alternatively, in acquired drug resistance, after initial treatment response, relapse of the disease might occur through clonal selection. Resistant cells that exist prior to treatment may expand due to treatment mediated selective pressures and eventually evolve further and acquire further mutations. Drug-tolerant persister (DTP) cells that acquire resistance mechanisms (without de novo genetic mutations) during therapy are a major stumbling block in achieving successful treatment. Such residual persistent cells are capable of adapting to their micro-environment where they can stay hidden for extended periods of time and in due course can act as a reservoir for the instigation of genetic resistance. The presence of DTP cells can vary across different types of therapeutic responses and a patient may possess more than one type of DTP cell within a single tumor and/or multiple metastases. At the macroscopic level, a patient may show complete response (tumor size reduced 100%) or partial response (≥30% metastases size reduction) or stable disease (sum of metastases size between −30% and +20%) or progressive disease (increased tumor size ≥ 20%). DTP cells are known to have characteristics such as epigenetic modifications, mitochondrial cellular energy modulation, symbiotic relationships with other malignant cells for survival benefit, modulation of surrounding tissue stromal cells, control of REDOX signaling and reactive oxygen species, influencing ribosomes and protein translation, resistance to cell death mechanisms, trans- differentiation and epithelial to mesenchymal transition capability, ability to modulate immune responses, and the ability to further mutate. Given these characteristics, we can categorize the ways in which persistent cancer cells can evade treatment into four often co-existing and non-mutually exclusive strategies: (a) adaptable cell metabolism, (b) modified cell proliferation, (c) changing cellular plasticity, and (d) modulating the microenvironment. Molecular mechanisms underlying distinct regulated cell death pathways show remarkable interconnectivity. This implies that targeting a single cell death pathway maybe ineffective in eliminating malignant cells and, therefore, activation of multiple cell death mechanisms and/or anti-cell survival mechanisms to target cancer cells may bring about improved anti-cancer responses, increased patient survival, and greater clinical success. Adopted from Refs. [191,192,197,198,199,201,202,204,209,213,217].