Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer

Knudsen, Erik S.; Kumarasamy, Vishnu; Ruiz, Amanda; Sivinski, Jared; Chung, Sung‐Jae; Grant, Adam; Vail, Paris; Chauhan, Shailender S.; Jie, Tun; Riall, Taylor S.; Witkiewicz, Agnieszka K.

doi:10.1038/s41388-018-0650-0

Cited by 50 publications

(51 citation statements)

References 51 publications

(72 reference statements)

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“…To determine the features of therapeutic cooperation, we interrogated canonical determinants of cell cycle control. Treatment with CDK4/6 inhibitors lead to the adaptive upregulation of cyclin D1 and cyclin E in the pancreatic cancer cell lines (Fig 1D), consistent with prior findings 37, 38 . These adaptive features of CDK4/6 inhibition were ameliorated with the combined treatment with trametinib that yielded potent blockade of RB phosphorylation and suppression of cyclin A expression (Fig 1D).…”

Section: Resultssupporting

confidence: 90%

“…In spite of genetic features that would be expected to yield sensitivity to CDK4/6 inhibitors pancreatic cancer cell lines are surprisingly resistant to this treatment 16, 37 . To systematically define cooperating agents, we carried out live cell imaging-based drug screens where the suppression of proliferation is directly monitored by evaluating cell number (Fig 1A and S1).…”

Section: Resultsmentioning

confidence: 99%

“…However, the lack no induction of IL6, IL8, and IL1ß in our data and little positive enrichment for the classical SASP signature (Fig S6). In addition to MEK inhibition, MTOR inhibitors can cooperate with CDK4/6 inhibitors in driving cell cycle exit 37 . The TORC1/2 inhibitor TAK228 results in potent cooperation with CDK4/6 inhibition in the suppression of cell cycle-regulated genes in PDX models and cell lines (Fig S7).…”

Section: Resultsmentioning

confidence: 99%

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Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Knudsen

Kumarasamy

Chung

et al. 2019

Preprint

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Pancreatic cancer harbors a poor prognosis due to the lack of effective systemic therapies. Here we interrogated means to target key effector pathways down-stream from KRAS. We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumor progression. These effects were associated with stable cell cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumor and host that can contribute to durable control for tumors in combination with immune checkpoint inhibitor therapy.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Knudsen

Kumarasamy

Chung

et al. 2019

Preprint

Self Cite

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“…PDX 99/810 comparison RNA sequencing was performed on triplicate PDX models for control and palbociclib treated samples. 18 RNA sequencing counts were normalized and logtransformed using the edgeR R package. Log-fold…”

Section: Biomarker Assessmentsmentioning

confidence: 99%

A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy

Weinberg

Wang

Witkiewicz

et al. 2020

Journal of Pancreatic Cancer

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Purpose: Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis. CDK4/6 is often deregulated in mPC due to CDKN2A loss, resulting in the loss of p16INK4a that inhibits CDK4/6. CDK4/6 inhibitor monotherapy is ineffective due to RAS-mediated activation of alternative pathways, including phosphatidylinositol 3-kinasemammalian target of rapamycin (PI3K-mTOR). We conducted a phase I study combining CDK4/6 and mTOR inhibition in patients with mPC refractory to standard chemotherapy. Materials and Methods: The combination of ribociclib (a CDK4/6 inhibitor) and everolimus (an mTOR inhibitor) was investigated in a phase I study in patients with mPC and progression on 5-fluorouracil-and gemcitabinebased chemotherapy. A 3 + 3 design was used to find the recommended phase II dose (RP2D) of ribociclib (250 or 300 mg daily for days 1-21) in combination with everolimus (2.5 mg daily for days 1-28) every 28 days. Secondary endpoints were median progression-free survival (mPFS), median overall survival (mOS), response rate, safety, and effect on the retinoblastoma pathway. Results: Twelve patients were enrolled, six at each dose level. Only one patient had a dose-limiting toxicity of a grade 3 rash at the 250 mg dose. The RP2D of ribociclib was 300 mg. mPFS was 1.8 months (95% confidence interval [CI] [0.6-2.1]), and mOS was 3.7 months (95% CI [2.3-5.6]). Two patients (17%) had stable disease at 8 weeks. Pharmacodynamic evaluation demonstrated that CDK4/6-regulated gene expression was significantly decreased on treatment (n = 6, p < 0.001). Conclusion: Ribociclib 300 mg daily for days 1-21 plus everolimus 2.5 mg daily was well tolerated and associated with decreased CDK4/6-regulated gene expression. This combination was not effective as a third-line therapy but does pharmacologically target CDK4/6 in mPC, revealing the potential for benefit in other settings.

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“…Previous studies have elucidated that CDK6 could phosphorylate Rb protein, induces the expression of E2F1, thus inducing the transformation from G1 to S phase, promoting cell proliferation and acting as a tumor promotor in human cancer [34]. Indeed, CDK6 has been found to be abnormally expressed in various types of malignant tumors such as bladder cancer [35] and pancreatic cancer [36], and be a mediator in the regulation of them. For example, CDK6 was recognized as a target of lncRNA HNF1A-AS1/miR-149-5p axis in the modulation of cell proliferation, cell cycle, invasion, and migration of nonsmall cell lung cancer cells [37].…”

Section: Discussionmentioning

confidence: 99%

Identification of UAP1L1 as tumor promotor in gastric cancer through regulation of CDK6

Liu

et al. 2020

Aging

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Gastric cancer (GC) is one of the most commonly diagnosed malignancies in digestive tract and its underlying molecular mechanism is still not clear, so we aimed to reveal the relationship between GC and UDP-GlcNAc pyrophosphorylase-1 like 1 (UAP1L1). The detection of UAP1L1 expression in GC tumor and normal tissues was accomplished by immunohistochemistry and demonstrated the upregulation of UAP1L1 in GC, which was statistically associated with tumor grade. GC cell models constructed via transfection of UAP1L1-silencing/ overexpressing lentiviruses were employed for evaluating the effects of UAP1L1 knockdown/overexpression on GC in vitro and in vivo. The results indicated that UAP1L1 played important role in development of GC through regulating cell proliferation, colony formation, cell apoptosis and cell migration. Subsequently, CDK6 was identified as a potential target in UAP1L1 induced regulation of GC, downregulation of which exhibited similar inhibition effects on GC with UAP1L1. Moreover, it was demonstrated that the promotion of GC by UAP1L1 overexpression could be significantly attenuated or even reversed by simultaneously silencing CDK6. In conclusion, UAP1L1 was reported to be a tumor promotor in the development and progression of GC which may exert its role through regulating CDK6 and may act as a candidate of therapeutic target in treatment.

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Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer

Cited by 50 publications

References 51 publications

Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy

Identification of UAP1L1 as tumor promotor in gastric cancer through regulation of CDK6

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