Therapeutic targeting of replicative immortality

Abstract

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.

Keywords: Oncogenic stress; Senescence; Telomerase; p53; pRB.

Fig. 1

A simplified scheme is presented of hypothetical alternative phosphorylation states and growth arrest functions of RB family proteins. Gray circles represent phosphate groups added to RB family proteins by different cyclin-CDK complexes. The primary sites of action of endogenous CDK inhibitors, p16 and p21, as well as the small molecule inhibitor, PD0332991, are also shown.

Fig. 2

The senescence associated secretory phenotype (SASP) aids in the clearance of senescent cells, but can potentially promote proliferation of tumor cells that are not stably growth arrested. Cell-autonomous growth arrest associated with senescence prevents the proliferation of damaged cells and is at least partially dependent on p53/pRB pathways. In normal tissues, senescence also results in the activation of non-autonomous secretory factors that participate in wound response signaling, culminating in senescent cell clearance and tissue repair (left panel). In cancer tissues (right panel), activation of non-autonomous secretory factors can be altered and/or increased by treatment with therapeutic agents. However, cancer cells often harbor compromised p53/pRB pathways, and as a result, growth arrest may not occur or may be less stable. Alterations in the types or abundance of secretory factors released by such cells may interfere with immune clearance and/or stimulate the growth of nearby cancer cells that have escaped cell death. Important questions regarding the impact of senescence in the context of cancer therapy are highlighted in red.

Fig. 3

Mediators of hTERT activation and repression. Green arrows (top panel) indicate reported interactions that activate, while red arrows (bottom panel) indicate reported interactions that inhibit hTERT. Letters indicate mechanism (TR, transcriptional regulation; B, binding; -/+P, de/phosphorylation; IE, influence on expression).