WEE1 inhibitor, AZD1775, overcomes trastuzumab resistance by targeting cancer stem-like properties in HER2-positive breast cancer

Sand, Andrea; Piacsek, Mitchel; Donohoe, Deborah; Duffin, Aspen T.; Riddell, Geoffrey T.; Sun, Chaoyang; Tang, Ming; Rovin, Richard; Tjoe, Judy A.; Yin, Jun

doi:10.1016/j.canlet.2019.12.023

Cited by 34 publications

(27 citation statements)

References 45 publications

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“…The WEE-1 inhibitor, AZD1775 (MK1775), has been included in several clinical trials ( Table 1 ) ( 219 ). It has been recently found to target CSC properties in breast cancer ( 241 ).…”

Section: Prospective Therapeutic Approaches Targeting Cscs In Mutant mentioning

confidence: 99%

Cancer Stemness: p53 at the Wheel

2021

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The tumor suppressor p53 maintains an equilibrium between self-renewal and differentiation to sustain a limited repertoire of stem cells for proper development and maintenance of tissue homeostasis. Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming. A few reports in recent years have indicated that prevalent TP53 oncogenic gain-of-function (GOF) mutations further boosts the stemness properties of cancer cells. In this review, we discuss the role of wild type p53 in regulating pluripotency of normal stem cells and various mechanisms that control the balance between self-renewal and differentiation in embryonic and adult stem cells. We also highlight how inactivating and GOF mutations in p53 stimulate stemness in cancer cells. Further, we have explored the various mechanisms of mutant p53-driven cancer stemness, particularly emphasizing on the non-coding RNA mediated epigenetic regulation. We have also analyzed the association of cancer stemness with other crucial gain-of-function properties of mutant p53 such as epithelial to mesenchymal transition phenotypes and chemoresistance to understand how activation of one affects the other. Given the critical role of cancer stem-like cells in tumor maintenance, cancer progression, and therapy resistance of mutant p53 tumors, targeting them might improve therapeutic efficacy in human cancers with TP53 mutations.

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“…The WEE-1 inhibitor, AZD1775 (MK1775), has been included in several clinical trials ( Table 1 ) ( 219 ). It has been recently found to target CSC properties in breast cancer ( 241 ).…”

Section: Prospective Therapeutic Approaches Targeting Cscs In Mutant mentioning

confidence: 99%

Cancer Stemness: p53 at the Wheel

2021

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“…As BIM is downstream of both the PI3K and RAS/MAPK pathways, this is to be expected. Most of these pathway disturbance after PARPi have been validated in vitro or in vivo models in our and others previous works 16,[19][20][21] , which will be illustrated in detail below.…”

Section: Adaptive Response After Parpi Evaluated By Rppamentioning

confidence: 94%

“…Then cell lysates were evaluated by RPPA with 218 antibodies targeting total and phosphorylated proteins. In order to validate the generalization of the adaptive response and eliminate off-target effects after PARPi, we integrated results of protein alterations following both BMN673 and AZD2281 as we published previously 16,19 . First, we averaged the duplications under each treatment condition.…”

Section: Adaptive Response After Parpi Evaluated By Rppamentioning

confidence: 99%

Systems approach to rational combination therapy: PARP inhibitors

Sun

Fang

Labrie

et al. 2020

Biochemical Society Transactions

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Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated activity across a broad spectrum of molecular backgrounds and tumor types, with the greatest activity observed in patients with aberrations in the homologous recombination DNA damage repair pathway. Despite remarkable responses in a subset of patients, the response is usually modest and transient due to the almost inevitable emergence of resistance. Tumors develop resistance through rapid adaptation to the effects of PARPi as well as by generation or selection of genomic aberration. Although adaptive responses results in drug resistance, it also induces therapeutic vulnerabilities that could be exploited with rational combination therapies. To fulfill this role, we established the combinatorial adaptive response therapy (CART) platform by performing reverse-phase protein arrays to characterize adaptive responses, and develop rational combination therapies. Our series of studies strongly support the efficacy of this strategy, wherein targeting the emerging adaptive responses to PARPi with MEK/ERK inhibitors, WEE1/ATR inhibition (inhibitors of S-phase and G2 DNA damage checkpoint), and PI3K/AKT/mTOR inhibition, and showed promising anti-tumor activity in various preclinical models. Importantly, this approach has been proven highly efficient, and several combinational therapies developed from the CART platform are being evaluated in ongoing clinical trials (NCT03801369, NCT03586661, NCT03162627, NCT03544125, NCT02659241, NCT02208375, NCT02316834, and NCT03637491).

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“…Thus, targeting upstream of JAK/STAT3 pathway, for instance IL-6 receptor antibody, could inhibit trastuzumab resistance and reduce the CSC population. A previous study showed that an excellent functional biomarker for trastuzumab resistance is Mucin1 (MUC1), and its cleaved form is named MUC1* (Sand et al, 2020). Interestingly, anti-MUC1* was found to have a dramatic, stimulatory effect on stem cell growth (Hikita et al, 2008).…”

Section: Trastuzumab Resistancementioning

confidence: 99%

The Breast Cancer Stem Cells Traits and Drug Resistance

et al. 2021

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Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.

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WEE1 inhibitor, AZD1775, overcomes trastuzumab resistance by targeting cancer stem-like properties in HER2-positive breast cancer

Cited by 34 publications

References 45 publications

Cancer Stemness: p53 at the Wheel

Cancer Stemness: p53 at the Wheel

Systems approach to rational combination therapy: PARP inhibitors

The Breast Cancer Stem Cells Traits and Drug Resistance

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