Replication stress response in cancer stem cells as a target for chemotherapy

Self Cite

131

PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.

Section: Introductionmentioning

confidence: 99%

PTEN Tumor-Suppressor: The Dam of Stemness in Cancer

Luongo

Colonna

Calapà

et al. 2019

Self Cite

131

“…At the mechanistic level, in this study, we demonstrated that combined inhibition of CHK1 and either MRE11 or RAD51 leads to uncontrolled cell cycle progression and untimely mitotic entry of cells with ongoing replication stress. Usually, the proliferation of replication stressed cells is limited by the activation of the intra-S and G 2 /M checkpoint, both of which depend on the ATR-CHK1 axis [35,36] and, so, are silenced on its abrogation. Consistently, under prexasertib-based regimens, we found illicit proliferation and mitotic entry of CRC-SCs with unreplicated and damaged DNA, as shown by the presence of premature mitoses (pH3 + cells with DNA content between 2n and 4n) and of mitotic damage (mitotic cells displaying γH2AX foci).…”

Section: Discussionmentioning

confidence: 99%

The Targeting of MRE11 or RAD51 Sensitizes Colorectal Cancer Stem Cells to CHK1 Inhibition

Mattiello

Rehim

Musella

et al. 2021

Self Cite

Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients.

“…Intriguingly, loss of RAD52 strongly impairs viability of checkpointdeficient cells [102]. Since CHK1 inhibitors are being tested in clinical trials [129][130][131], combining RAD52 and CHK1 inhibition might prove a much more effective strategy to kill cancer cells, especially cancer stem cells. RAD52 might be involved in repair of the resulting, MUS81-dependent, DSBs by BIR or, alternatively, by SSA.…”

Section: Conclusion and Potential Implications Of Replication Fork-rmentioning

confidence: 99%

Physiological and Pathological Roles of RAD52 at DNA Replication Forks

Malacaria

Honda

Franchitto

et al. 2020

Understanding basic molecular mechanisms underlying the biology of cancer cells is of outmost importance for identification of novel therapeutic targets and biomarkers for patient stratification and better therapy selection. One of these mechanisms, the response to replication stress, fuels cancer genomic instability. It is also an Achille's heel of cancer. Thus, identification of pathways used by the cancer cells to respond to replication-stress may assist in the identification of new biomarkers and discovery of new therapeutic targets. Alternative mechanisms that act at perturbed DNA replication forks and involve fork degradation by nucleases emerged as crucial for sensitivity of cancer cells to chemotherapeutics agents inducing replication stress. Despite its important role in homologous recombination and recombinational repair of DNA double strand breaks in lower eukaryotes, RAD52 protein has been considered dispensable in human cells and the full range of its cellular functions remained unclear. Very recently, however, human RAD52 emerged as an important player in multiple aspects of replication fork metabolism under physiological and pathological conditions. In this review, we describe recent advances on RAD52's key functions at stalled or collapsed DNA replication forks, in particular, the unexpected role of RAD52 as a gatekeeper, which prevents unscheduled processing of DNA. Last, we will discuss how these functions can be exploited using specific inhibitors in targeted therapy or for an informed therapy selection.Cancers 2020, 12, 402 2 of 17 for all known homology-directed DNA repair mechanisms in yeast [11,13,14], mammalian RAD52 was previously considered to be dispensable for recombination-based DNA repair and its knock out in mouse does not show any lethality or other remarkable phenotypes as those associated with the RAD51 knock out [15,16]. Based on the studies in chicken DT40 cells [16,17], it has been proposed that the vertebrate RAD52 may be involved only in a limited subset of the recombinational DNA repair events. Indeed, the most crucial recombination mediator function of yeast Rad52 is played by BRCA2 tumor suppressor protein in higher eukaryotes, including mammals, fungi, and plants [18][19][20].Remarkably, much interest in RAD52 function arose since its deficiency has been shown to be synthetic lethal with biallelic mutations in or absence of BRCA1/2 or BRCA-related genes [13,[21][22][23], which are found mutated or de-regulated in many hereditary and sporadic breast and ovarian cancers [24,25].While biochemical features of RAD52, its more novel double-strand break (DSB) repair functions and its modifications are the focus of other reviews in this issue [12,[26][27][28], here, we will discuss the unexpected roles that RAD52 plays at the DNA replication fork and their implications for cancer therapy. Role of RAD52 in DSBs Repair