Taxanes in cancer treatment: Activity, chemoresistance and its overcoming

The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug-inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.

Mechanisms of Taxane Resistance

The actin and microtubule cytoskeletons comprise a variety of networks with distinct architectures, dynamics and protein composition. A fundamental question in eukaryotic cell biology is how these networks are spatially and temporally controlled, so they are positioned in the right intracellular places at the right time. While significant progress has been made in understanding the self-assembly of actin and microtubule networks, less is known about how they are patterned and regulated in a site-specific manner. In mammalian systems, septins are a large family of GTP-binding proteins that multimerize into higher-order structures, which associate with distinct subsets of actin filaments and microtubules, as well as membranes of specific curvature and lipid composition. Recent studies have shed more light on how septins interact with actin and microtubules, and raised the possibility that the cytoskeletal topology of septins is determined by their membrane specificity. Importantly, new functions have emerged for septins regarding the generation, maintenance and positioning of cytoskeletal networks with distinct organization and biochemical makeup. This Review presents new and past findings, and discusses septins as a unique regulatory module that instructs the local differentiation and positioning of distinct actin and microtubule networks.

/pdf/spatial-effects-site-specific-regulation-of-actin-and-2e72ca8i7b.pdf

Spatial effects - site-specific regulation of actin and microtubule organization by septin GTPases.

Septins are GTP-binding proteins that are evolutionarily and structurally related to the RAS oncogenes. Septin expression levels are altered in many cancers and new advances point to how abnormal septin expression may contribute to the progression of cancer. In contrast to the RAS GTPases, which are frequently mutated and actively promote tumorigenesis, little is known about the occurrence and role of septin mutations in human cancers. Here, we review septin missense mutations that are currently in the Catalog of Somatic Mutations in Cancer (COSMIC) database. The majority of septin mutations occur in tumors of the large intestine, skin, endometrium and stomach. Over 25% of the annotated mutations in SEPT2, SEPT4 and SEPT9 belong to large intestine tumors. From all septins, SEPT9 and SEPT14 exhibit the highest mutation frequencies in skin, stomach and large intestine cancers. While septin mutations occur with frequencies lower than 3%, recurring mutations in several invariant and highly conserved amino acids are found across different septin paralogs and tumor types. Interestingly, a significant number of these mutations occur in the GTP-binding pocket and septin dimerization interfaces. Future studies may determine how these somatic mutations affect septin structure and function, whether they contribute to the progression of specific cancers and if they could serve as tumor-specific biomarkers.

/pdf/septin-mutations-in-human-cancers-3ldq8fjssn.pdf

Septin Mutations in Human Cancers.

Polarity of Neuronal Membrane Traffic Requires Sorting of Kinesin Motor Cargo during Entry into Dendrites by a Microtubule-Associated Septin.

Cancer cell resistance to taxanes is a complex, multifactorial process, which results from the combination of several molecular and cellular changes. In breast cancer cells adapted to long-term paclitaxel treatment, we previously identified a new adaptive mechanism that contributes to resistance and involves high levels of tubulin tyrosination and long-chain polyglutamylation coupled with high levels of septin expression, especially that of SEPT9_i1. This in turn led to higher CLIP-170 and MCAK recruitment to microtubules to enhance microtubule dynamics and therefore counteract the stabilizing effects of taxanes. Here, we explored to which extent this new mechanism alone could trigger taxane resistance. We show that coupling septins (including SEPT9_i1) overexpression together with long-chain tubulin polyglutamylation induce significant paclitaxel resistance in several naive (taxane-sensitive) cell lines and accordingly stimulate the binding of CLIP-170 and MCAK to microtubules. Strikingly, such resistance was paralleled by a systematic relocalization of septin filaments from actin fibers to microtubules. We further show that this relocalization resulted from the overexpression of septins in a context of enhanced tubulin polyglutamylation and reveal that it could also be promoted by an acute treatment with paclitaxel of sensitve cell displaying a high basal level of SEPT9_i1. These findings point out the functional importance and the complex cellular dynamics of septins in the onset of cell resistance to death caused by microtubule-targeting antimitotic drugs of the taxane family.

/pdf/septin-filament-coalignment-with-microtubules-depends-on-9pbdfrqwr7.pdf

Septin filament coalignment with microtubules depends on SEPT9_i1 and tubulin polyglutamylation, and is an early feature of acquired cell resistance to paclitaxel.

The mechanisms of cancer cell adaptation to the anti-microtubule agents of the taxane family are multifaceted and still poorly understood. Here, in a model of breast cancer cells which display amplified microtubule dynamics to resist Taxol®, we provide evidence that septin filaments containing high levels of SEPT9_i1 bind to microtubules in a way that requires tubulin long chain polyglutamylation. Reciprocally, septin filaments provide a scaffold for elongating and trimming polyglutamylation enzymes to finely tune the glutamate side-chain length on microtubules to an optimal level. We also demonstrate that tubulin retyrosination and/or a high level of tyrosinated tubulin is crucial to allow the interplay between septins and polyglutamylation on microtubules and that together, these modifications result in an enhanced CLIP-170 and MCAK recruitment to microtubules. Finally, the inhibition of tubulin retyrosination, septins, tubulin long chain polyglutamylation or of both CLIP-170 and MCAK allows the restoration of cell sensitivity to taxanes, providing evidence for a new integrated mechanism of resistance.

/pdf/septin-cooperation-with-tubulin-polyglutamylation-22szw3bt4o.pdf

Septin cooperation with tubulin polyglutamylation contributes to cancer cell adaptation to taxanes.

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Septin filament coalignment with microtubules depends on SEPT9_i1 and tubulin polyglutamylation, and is an early feature of acquired cell resistance to paclitaxel.

Septin cooperation with tubulin polyglutamylation contributes to cancer cell adaptation to taxanes.