Cancer cell cycle dystopia: heterogeneity, plasticity, and therapy

Abstract

The mammalian cell cycle has been extensively studied regarding cancer etiology, progression, and therapeutic intervention. The canonical cell cycle framework is supported by a plethora of data pointing to a relatively simple linear pathway in which mitogenic signals are integrated in a stepwise fashion to allow progression through G1/S with coordinate actions of cyclin-dependent kinases (CDK)4/6 and CDK2 on the RB tumor suppressor. Recent work on adaptive mechanisms and intrinsic heterogeneous dependencies indicates that G1/S control of the cell cycle is a variable signaling pathway rather than an invariant engine that drives cell division. These alterations can limit the effectiveness of pharmaceutical agents but provide new avenues for therapeutic interventions. These findings support a dystopian view of the cell cycle in cancer where the canonical utopian cell cycle is often not observed. However, recognizing the extent of cell cycle heterogeneity likely creates new opportunities for precision therapeutic approaches specifically targeting these states.

Keywords: CDK4; CDK6; CHK1; RB; abemaciclib; ambra1; aurora kinase; cyclin D1; cyclin E; p16(INK4A); p27(KIP1); palbociclib.

Figure 1.. Genetic alterations of G1/S cell cycle genes in cancer.

(A) Oncoprint summarizes the frequency of genetic alterations of the indicated genes in TCGA (The Cancer Genome Atlas) Pan-Cancer Cohort. (B) Barplots summarize the five histological tumor types with the most frequent disruption of a given gene, Color codes: blue, homozygous deletion; red, gene amplification; green, gene mutation; orange, insertion/deletion. Abbreviations: AMP, amplification; HOMO DEL, homozygous deletion; INDEL, insertion/deletion; SNV, single-nucleotide variant. TCGA study abbreviations in panel (B) are given in https://gdc.cancer.gov/resources-tcga-users/tcga-code-tables/tcga-study-abbreviations.

Figure 2.. The canonical G1/S pathway.

(A) Timeline summarizing discoveries which contributed to the development of the canonical regulation of G1/S progression. (B) Basic schematic of canonical G1/S control wherein mitogenic and oncogenic signals converge on CDK4/6–cyclin D activity. Although these factors support the assembly and activation of the complexes, select oncogenic signaling can induce p16^INK4A to yield oncogene-induced senescence. The activation of CDK4/6 initiates the phosphorylation of RB and enables the subsequent activation of CDK2/cyclin E that contributes to the hyperphosphorylation and functional inactivation of RB. p27^KIP1 plays a complex role in CDK4/6 activation state, but is a potent CDK2 inhibitor. With RB inactivation, E2F-mediated transcription elicits a program of gene expression to drive progression through the remainder of the cell cycle. Adapted from [116].

Figure 3.. Mechanisms of resistance to CDK4/6 inhibitors.

(A) The table summarizes different genetic events that are associated with resistance to CDK4/6 inhibition. (B) The presumed mechanistic consequences for the cell cycle are summarized. The schematic represents different nodes through which CDK4/6 inhibition is coupled to suppression of CDK2 activity, whereas select CDK6 complexes and CDK2/cyclin D1 complexes are resistant to the action of the FDA-approved inhibitors.

Figure 4.. Differential mechanisms for the control of RB-deficient cell cycles.

There appear to be at least two different RB-deficient cell cycles. One is cyclin E-dependent, and controls the phosphorylation of p130. In the second the mechanisms controlling p130 phosphorylation to drive G1/S progression are unknown.

Figure 5.. Distinct G1/S CDK and cyclin dependencies in cancer cells.

(A) The boxplot summarizes the requirement for the indicated CDK or cyclin as determined from DepMAP data. The CERES (CRISPR/Cas essentiality screen) score is an indication of essentiality, but there is substantial heterogeneity in the requirements for different CDK and cyclin gene in different CRISPR screens. (B) The heatmap illustrates the differential requirement for select CDK or cyclin genes as determined by clustering based on the CERES score. Darker blue indicates a larger magnitude of effect, as summarized in the color bar. (C) Schematic representation of different RB-proficient cell cycles that have been uncovered through screens and functional analyses.