The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Medico, Enzo; Russo, Mariangela; Picco, Gabriele; Cancelliere, Carlotta; Valtorta, Emanuele; Corti, Giorgio; Buscarino, Michela; Isella, Claudio; Lamba, Simona; Martinoglio, Barbara; Veronese, Silvio; Siena, Salvatore; Sartore-Bianchi, Andrea; Beccuti, Marco; Mottolese, Marcella; Linnebacher, Michael; Cordero, Francesca; Nicolantonio, Federica Di; Bardelli, Alberto

doi:10.1038/ncomms8002

Cited by 263 publications

(338 citation statements)

References 46 publications

(62 reference statements)

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“…Several studies show that CRC cell lines recapitulate the main molecular phenotypes observed in primary CRC (Ahmed et al ., 2013; Barretina et al ., 2012; Berg et al ., 2017; Medico et al ., 2015; Mouradov et al ., 2014), which substantiate their value as preclinical model systems to assess a variety of pharmacogenomic relationships. Consistent with the observed clinical benefit in patients with CDX2‐negative tumors in stage III, loss of CDX2 expression was strongly associated with sensitivity to conventional chemotherapeutics in vitro , both in our drug screen dataset and in a large public dataset, again independent of MSI status.…”

Section: Discussionmentioning

confidence: 99%

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

et al. 2018

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We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I–IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5‐year relapse‐free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I–III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF‐mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5‐year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2‐negative cell lines were significantly more sensitive to chemotherapeutics than CDX2‐positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2‐negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early‐stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.

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Section: Discussionmentioning

confidence: 99%

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

et al. 2018

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“…Although the frequency of ALK fusions in colorectal carcinoma is low, the incidence of 0.2% translates into approximately 265 patients in the United States each year and approximately 2,800 patients worldwide each year. The relatively broad range of ALK fusion frequencies in colorectal cancer varying from 0.13% to 2.5% described in previous studies (Supplementary Table S1) may be related to different patient cohorts analyzed, in some studies limited to 40 cases, and different testing methodologies, including IHC, FISH, real-time PCR, exon array, comprehensive genomic profiling, and transcriptome analysis (6,7,(11)(12)(13)(14)(15). In contrast, in this study, ALK rearrangements were identified in a cohort of 3,157 patients with colorectal carcinoma using CGP and cohort of 2,980 patients with colorectal carcinoma by IHC.…”

Section: Discussionmentioning

confidence: 99%

“…Among the epithelial cancers they are most common in non-small cell lung cancer (NSCLC), comprising approximately 3% to 7% of lung adenocarcinoma (10), while only nine cases of colorectal carcinoma harboring ALK fusions have been described in seven previous studies (refs. 6,7,(11)(12)(13)(14)(15)Supplementary Table 1). Tumors with ALK rearrangements express activated fusion kinases composed of the intact ALK tyrosine kinase domain fused with different unrelated gene partners.…”

Section: Introductionmentioning

confidence: 99%

“…The ALK inhibitors crizotinib and ceritinib have become standard of care for ALKdriven lung cancer, with superior efficacy and improved tolerability, in comparison with cytotoxic drugs (17,18). In two preclinical studies, the growth of colorectal carcinoma cell lines harboring EML4-ALK fusions was inhibited by the ALK inhibitors crizotinib and entrectinib (7,15).…”

Section: Introductionmentioning

confidence: 99%

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Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

Yakirevich

Resnick

Mangray

et al. 2016

Clinical Cancer Research

111

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Purpose: Chromosomal translocations in the anaplastic lymphoma kinase (ALK) gene have been identified as oncogenic drivers in lung adenocarcinomas and other tumors, recently including rare cases of colorectal carcinoma. We identified a patient with refractory metastatic colorectal carcinoma harboring a STRN-ALK gene fusion who achieved an exceptional clinical benefit to the ALK inhibitor ceritinib. Our goal was to further define the clinicopathologic features of ALK-rearranged colorectal carcinoma in a large cohort.Experimental Design: Clinical cases of colorectal carcinoma evaluated by comprehensive genomic profiling (CGP) or by ALK immunohistochemistry (IHC) were reviewed retrospectively. FISH and microsatellite instability (MSI) analyses were performed.Results: Nine colorectal carcinoma cases harbored ALK gene fusions. Six cases were identified by CGP of 3,157 colorectal carcinoma (0.2%) and three by IHC of 2,980 colorectal carcinoma (0.1%). The ALK fusions involved known ALK partners EML4, C2orf44, CAD, and the novel STRN, PPP1R21, SENPF, MAPRE3, and PRKAP1B partners. These advanced-stage colorectal carcinomas lacked mutations in other oncogenic drivers, predominantly involved the proximal colon, and often exhibited MSI and mucinous phenotype. The index patient was treated with the ALK inhibitor ceritinib, resulting in a marked decrease in size of a skin metastasis, and resolution by computerized tomography of all contrast enhancing tumor. After 9 months of treatment, biopsy of progressive disease demonstrated a KRAS mutation, consistent with acquired resistance to ceritinib.Conclusions: Colorectal carcinoma harboring ALK fusions represent a rare aggressive subtype of colorectal carcinoma with distinct clinicopathologic features. This report provides the first clinical evidence that such patients may benefit from targeted monotherapy with ALK inhibitors. Clin Cancer Res; 22(15); 3831-40.Ó2016 AACR.

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“…We and others have previously reported that colorectal cancer cell models harboring NTRK1 translocations are sensitive to NTRK1 silencing and to TRKA (protein encoded by the NTRK1 gene) kinase inhibition (5)(6)(7). Based on this, the patient was enrolled in the phase I ALKA clinical trial (EudraCT Number 2012-000148-88) of the pan-TRK kinase inhibitor entrectinib, a fi rst-in-class drug currently undergoing clinical testing ( 3 ).…”

Section: Acquired Resistance To Trka Inhibition In a Patient With Colmentioning

confidence: 99%

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

Russo

Misale

Ge³

et al. 2016

Cancer Discovery

Self Cite

271

272

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Entrectinib is a fi rst-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profi ling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1 , p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confi rmed that either mutation renders the TRKA kinase insensitive to entrectinib. These fi ndings can be immediately exploited to design next-generation TRKA inhibitors. SIGNIFICANCE:We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identifi cation of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the fi rst time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements. Cancer Discov; 6(1);[36][37][38][39][40][41][42][43][44]

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The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Cited by 263 publications

References 46 publications

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

Oncogenic ALK Fusion in Rare and Aggressive Subtype of Colorectal Adenocarcinoma as a Potential Therapeutic Target

Acquired Resistance to the TRK Inhibitor Entrectinib in Colorectal Cancer

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