A metastatic colon adenocarcinoma harboring BRAF V600E has a durable major response to dabrafenib/trametinib and chemotherapy

Williams, Casey; McMahon, Caitlin; Ali, Siraj M.; Abramovitz, Mark; Williams, Kirstin; Klein, Jessica; McKean, Heidi; Yelensky, Roman; George, Thomas J.; Elvin, Julia A.; Soman, Salil; Lipson, Doron; Chmielecki, Juliann; Morosini, Deborah; Miller, Vincent A.; Stephens, Philip J.; Ross, Jeffrey S.; Leyland‐Jones, Brian

doi:10.2147/ott.s90766

Cited by 7 publications

(4 citation statements)

References 15 publications

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“…Corcoran et al demonstrated a positive response to dual inhibition with dabrafenib and trametinib in a subset of 43 mCRC patients with the BRAF V600E mutation [ 61 ] (NCT 01072175 [ 55 ]). A case report corroborated the efficacy of this targeted agent combination successfully employed for the treatment of a BRAF -mutated mCRC patient that rapidly progressed after the failure of multiple systemic chemotherapy regimens [ 63 ]. The efficacy of dabrafenib administered in combination with both MEK and EGFR inhibitors (trametinib and panitumumab, respectively) is now under investigation in a phase II trial including 170 mCRC subjects with the BRAF V600E mutation.…”

Section: Emerging Target Molecules In Mcrc Treatmentmentioning

confidence: 93%

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

Bignucolo

Mattia

Cecchin

et al. 2017

IJMS

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The use of targeted agents in the treatment of metastatic colorectal cancer (CRC) has improved patient outcomes. Anti-epidermal growth factor receptor (anti-EGFR) agents (cetuximab and panitumumab) and antiangiogenic molecules (bevacizumab, regorafeninb, ramucirumab, and aflibercept) have been successfully integrated into clinical practice. Other drugs have been designed to target additional deregulated pathways in CRC, such as MAPK (mitogen-activated protein kinase)/PI3K-AKT (phosphatidylinositol-3-kinase-AKT serine/threonine kinase)/mTOR (mammalian target of rapamycin), HER-2 and 3 ( human epidermal growth factor receptor-2 and -3), and BRAF. A major issue with targeted treatment is early identification of patients with primary or secondary drug resistance. Pharmacogenomic research has demonstrated its value in this field, highlighting some tumor mutations that could discriminate responders from non-responders. The tumor genetic profile of the RAS/RAF pathway is needed before treatment with anti-EGFR agents; mutations in EGFR pathway genes have also been explored in relation to antiangiogenic molecules although further data are required prior to their integration into clinical practice. The introduction of immunotherapy has paved the way for a new generation of predictive markers, including genome-wide assessment of the tumor landscape. Furthermore, the development of next generation sequencing technology and non-invasive approaches to analyze circulating tumor DNA will make real-time monitoring of the tumor pharmacogenomic markers possible in the clinical routine, rendering precision medicine available to every patient.

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Section: Emerging Target Molecules In Mcrc Treatmentmentioning

confidence: 93%

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

Bignucolo

Mattia

Cecchin

et al. 2017

IJMS

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“…The BRAF V600 mutant inhibitor dabrafenib 58,59 is also a potent CDK16 inhibitor 18 . Accordingly, it promotes p27 accumulation in the BRAF -mutant colon cancer cell line HT-29 (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Phosphoregulation of the oncogenic protein regulator of cytokinesis 1 (PRC1) by the atypical CDK16/CCNY complex

et al. 2019

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CDK16 (also known as PCTAIRE1 or PCTK1) is an atypical member of the cyclin-dependent kinase (CDK) family that forms an active complex with cyclin Y (CCNY). Although both proteins have been recently implicated in cancer pathogenesis, it is still unclear how the CDK16/CCNY complex exerts its biological activity. To understand the CDK16/CCNY network, we used complementary proteomic approaches to identify potential substrates of this complex. We identified several candidates implicating the CDK16/CCNY complex in cytoskeletal dynamics, and we focused on the microtubule-associated protein regulator of cytokinesis (PRC1), an essential protein for cell division that organizes antiparallel microtubules and whose deregulation may drive genomic instability in cancer. Using analog-sensitive (AS) CDK16 generated by CRISPR-Cas9 mutagenesis in 293T cells, we found that specific inhibition of CDK16 induces PRC1 dephosphorylation at Thr481 and delocalization to the nucleus during interphase. The observation that CDK16 inhibition and PRC1 downregulation exhibit epistatic effects on cell viability confirms that these proteins can act through a single pathway. In conclusion, we identified PRC1 as the first substrate of the CDK16/CCNY complex and demonstrated that the proliferative function of CDK16 is mediated by PRC1 phosphorylation. As CDK16 is emerging as a critical node in cancer, our study reveals novel potential therapeutic targets.

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“…This has mostly worked in malignant melanoma, but no large series are available yet. Results for the BRAF inhibitor + MEK inhibitor combination for BRAF-mutant mCRCs are not well known, but data in case reports seem promising [ 22 ]. The combination is so promising that a phase 1-2 clinical trial for the combination of BRAF/MEK/EGFR inhibitors with 5-FU for treatment of BRAF-mutant mCRCs is still ongoing; the combination of these four drugs seems the most sensible one.…”

Section: Discussionmentioning

confidence: 99%

BRAF Inhibitors for BRAF V600E Mutant Colorectal Cancers: Literature Survey and Case Report

Peker¹,

Can²,

Özerhan³

et al. 2018

Case Reports in Surgery

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The main method of fighting against colon cancer is targeted treatment. BRAF inhibitors, which are accepted as standard treatment for V600E mutant malign melanomas, are the newest approach for targeted treatment of V600E mutant colorectal cancers. In this case report, we share our experience about the use of BRAF inhibitor vemurafenib on a V600E mutant metastatic right colon adenocarcinoma patient. A 59-year-old male with only lung multiple metastatic V600E mutant right colon cancer presented to our clinic. The patient was evaluated and FOLFOX + bevacizumab treatment was initiated, which was then continued with vemurafenib. A remarkable response was achieved with vemurafenib treatment in which the drug resistance occurred approximately in the sixth month. Even though the patient benefited majorly from vemurafenib, he died on the 20th month of the diagnosis. The expected overall survival for metastatic V600E mutant colon adenocarcinoma patients is 4.7 months. BRAF inhibitors provide new treatment alternatives for V600E mutant colorectal cancers, with prolonged overall survival. BRAF inhibitors in combination with MEK inhibitors are reported as feasible treatment to overcome BRAF inhibitor drug resistance on which phase studies are still in progress. To conclude, BRAF inhibitors alone or in combination with other drugs provide a chance for curing BRAF V600E mutant colorectal cancer patients.

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A metastatic colon adenocarcinoma harboring BRAF V600E has a durable major response to dabrafenib/trametinib and chemotherapy

Cited by 7 publications

References 15 publications

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

Phosphoregulation of the oncogenic protein regulator of cytokinesis 1 (PRC1) by the atypical CDK16/CCNY complex

BRAF Inhibitors for BRAF V600E Mutant Colorectal Cancers: Literature Survey and Case Report

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