Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer

Camps, Jordi; Nguyen, Quang Tri; Padilla‐Nash, Hesed; Knutsen, Turid; McNeil, Nicole E.; Wangsa, Danny; Hummon, Amanda B.; Grade, Marian; Ried, Thomas; Difilippantonio, Michael J.

doi:10.1002/gcc.20699

Cited by 79 publications

(89 citation statements)

References 39 publications

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“…4). FGFR2 has been found to be amplified and overexpressed in the colon cancer cell line H716 (13). We found that ponatinib potently inhibited the growth of H716 cells with a GI 50 value of 7 nmol/L but did not affect the growth of Colo205 cells (430 nmol/L; Fig.…”

Section: Activity Of Ponatinib In Gastric Cancer Models With Fgfr2 Ammentioning

confidence: 64%

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Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

298

212

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Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC 50 values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC 50 values <40 nmol/L and inhibited cell growth with GI 50 (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL-driven models and plasma levels of ponatinib that exceed the IC 50 values for FGFR1-4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers.

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Section: Activity Of Ponatinib In Gastric Cancer Models With Fgfr2 Ammentioning

confidence: 64%

“…FGFR2 is amplified in 4% of breast cancers (5,8), 3% to 25% of gastric cancers (9)(10)(11)(12) and in colon cancer (13,14). In addition, activating mutations in FGFR2 and FGFR3 have been found in 10% of endometrial cancers (15)(16)(17) and about 60% of nonmuscle-invasive bladder tumors (18,19), respectively.…”

Section: Introductionmentioning

confidence: 99%

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

298

212

View full text Add to dashboard Cite

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“…Additionally, several studies have surveyed DNA copy number alterations (CNAs) in CRC, establishing that CIN tumors harbor numerous broad gains and losses, often affecting whole chromosome arms; common alterations include gain of chromosome arms 7p (EGFR), 8q (MYC), 11p, 13q, and 20q and loss of 1p, 4q, 5q (APC), 8p, 17p (TP53), and 18q (DCC, SMAD4) (10)(11)(12)(13). Because of the large number of genes spanned by most of these alterations, pinpointing new driver cancer genes has proven challenging.…”

mentioning

confidence: 99%

CDX2is an amplified lineage-survival oncogene in colorectal cancer

Salari¹,

Spulak²,

Cuff³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, "lineage-survival" oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/β-catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis.lineage dependency | lineage-addiction oncogene | 13q amplification | CDK8 | integrative genomics

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“…Its expression behavior is down regulating in cold thyroid nodules (CTNs) as reported [28]. GPM6A is not yet found with thyroid cancer.…”

Section: X-axis: Cancer Typesmentioning

confidence: 73%

Computational Analysis on the Role of GPM6A in Human Thyroid Cancer

Khalid¹,

Sameen²,

Malik³

et al. 2012

JDMGP

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Thyroid cancer is one of the major cancers around the world. In this study the whole thyroid genome is systematically scanned in order to hit those molecular targets which are highly associated with thyroid cancer. To achieve this goal bioinformatics methodologies are combined. These include the high throughput microarray analysis combined with Serial analysis of gene expression. The results obtained revealed Glycoprotein M6A (GPM6A) as a novel associated gene marker. It belongs to the glycoprotein's family which plays a major role in cell migration and also known as the major contributors in tumor formation. Moreover the biological pathway of GPM6A is not yet been defined. In this study by assessing the whole biological mechanism the pathway is also inferred .This new drug target will help the biologists in finding the early diagnosis and better treatment for the thyroid cancer patients. Journal of

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Integrative genomics reveals mechanisms of copy number alterations responsible for transcriptional deregulation in colorectal cancer

Cited by 79 publications

References 39 publications

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

CDX2is an amplified lineage-survival oncogene in colorectal cancer

Computational Analysis on the Role of GPM6A in Human Thyroid Cancer

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