Full Text Journal Articles by
Author Vishnu Kumarasamy

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Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows.

Patrick J Roberts, Vishnu Kumarasamy, Agnieszka K Witkiewicz, Erik S Knudsen,

Cyclin-dependent kinases 4 and 6 (CDK4/6) have emerged as important therapeutic targets. Pharmacologic inhibitors of these kinases function to inhibit cell-cycle progression and exert other important effects on the tumor and host environment. Because of their impact on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the ... Read more >>

Mol. Cancer Ther. (Molecular cancer therapeutics)
[2020, 19(8):1575-1588]

Cited: 0 times

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

Erik Knudsen, Vishnu Kumarasamy, Sejin Chung, Paris Vail, Stephanie Tzetzo, Amanda Ruiz, Mukund Seshadri, Scott Abrams, Jianmin Wang, Agnieszka Witkiewicz,

ABSTRACT 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. ... Read more >>

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

Erik S Knudsen, Vishnu Kumarasamy, Sejin Chung, Amanda Ruiz, Paris Vail, Stephanie Tzetzo, Jin Wu, Ram Nambiar, Jared Sivinski, Shailender S Chauhan, Mukund Seshadri, Scott I Abrams, Jianmin Wang, Agnieszka K Witkiewicz,

OBJECTIVE:This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer. DESIGN:Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic ... Read more >>

Gut (Gut)
[2020, :]

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p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition.

Keelan Z Guiley, Jack W Stevenson, Kevin Lou, Krister J Barkovich, Vishnu Kumarasamy, Tilini U Wijeratne, Katharine L Bunch, Sarvind Tripathi, Erik S Knudsen, Agnieszka K Witkiewicz, Kevan M Shokat, Seth M Rubin,

The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex ... Read more >>

Science (Science (New York, N.Y.))
[2019, 366(6471):]

Cited: 3 times

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Salinomycin and its derivatives as potent RET transcriptional inhibitors for the treatment of medullary thyroid carcinoma.

Tariq Alqahtani, Vishnu Muthuraj Kumarasamy, Adam Huczyński, Daekyu Sun,

Rearranged during transfection kinase (RET) is a validated molecular target in medullary thyroid cancer (MTC), as activating mutations in RET are often associated with the development of MTC. The present study reports the first preclinical characterization of salinomycin and selected analogs as potent RET transcriptional inhibitors. Reverse transcription‑PCR and immunoblotting revealed ... Read more >>

Int J Oncol (International journal of oncology)
[2020, 56(1):348-358]

Cited: 1 time

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Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer.

Vishnu Kumarasamy, Amanda Ruiz, Ram Nambiar, Agnieszka K Witkiewicz, Erik S Knudsen,

Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and limit therapeutic response. While CDK4/6 represents a downstream target of both KRAS mutation and loss of the CDKN2A tumor suppressor in PDAC, clinical and preclinical studies indicate that pharmacological CDK4/6 ... Read more >>

Oncogene (Oncogene)
[2020, 39(9):1831-1845]

Cited: 4 times

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

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

Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A that encodes an endogenous CDK4/6 inhibitor to bypass the RB-mediated cell cycle suppression. Analysis of a panel of patient-derived cell lines and matched xenografts indicated that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition that is not due ... Read more >>

Oncogene (Oncogene)
[2019, 38(18):3355-3370]

Cited: 5 times

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Synthesis of Constrained Heterocycles Employing Two Post-Ugi Cyclization Methods for Rapid Library Generation with In Cellulo Activity.

Nicholas McConnell, Zhigang Xu, Vishnu Kumarasamy, Daekyu Sun, Brendan Frett, Hong-Yu Li,

Benzimidazoles and quinoxalinones are present in the core of many pharmacologically relevant compounds. Several combinatorial methods have been developed to attach ring systems to both scaffolds for derivatization at select positions. Herein, we describe the development of novel constrained heterocyclic compounds attached to the N1 position of both benzimidazole and ... Read more >>

ChemistrySelect (ChemistrySelect)
[2017, 2(35):11821-11825]

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Demonstration of a potent RET transcriptional inhibitor for the treatment of medullary thyroid carcinoma based on an ellipticine derivative.

Vishnu Muthuraj Kumarasamy, Daekyu Sun,

Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as ... Read more >>

Int J Oncol (International journal of oncology)
[2017, 51(1):145-157]

Cited: 3 times

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Selective repression of RET proto-oncogene in medullary thyroid carcinoma by a natural alkaloid berberine.

Vishnu Muthuraj Kumarasamy, Yoon-Joo Shin, John White, Daekyu Sun,

The gain-of-function mutation of the RET proto-oncogene, which encodes a receptor tyrosine kinase, is strongly associated with the development of several medullary thyroid carcinomas (MTCs). Thus, the RET protein has been explored as an excellent target for progressive and advanced MTC. In this study we have demonstrated a therapeutic strategy ... Read more >>

BMC Cancer (BMC cancer)
[2015, 15:599]

Cited: 8 times

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