PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors.

Kopetz, Scott; Desai, J.; Chan, Err–Cheng; Hecht, J. Randolph; Pj, O'Dwyer; Lee, R. J.; Nolop, K. B.; Saltz, Leonard B.

doi:10.1200/jco.2010.28.15_suppl.3534

Cited by 240 publications

(181 citation statements)

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“…In an expansion cohort of the phase I study with vemurafenib at the RP2D, only 1 of 19 patients had a confirmed partial response (44). These findings support preclinical data suggesting that BRAF-mutant colorectal cancers might respond to combined targeted therapy with BRAF and EGFR inhibitors (45).…”

Section: Discussionsupporting

confidence: 75%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for specific aberrations (KRAS/BRAF/PIK3CA mutations, PTEN and pMET expression). Patients were subsequently offered phase I trials with matched targeted agents (MTA) directed at the identified anomalies. During 2010 and 2011, tumor molecular analysis was conducted in 254 patients: KRAS mutations (80 of 254, 31.5%), BRAF mutations (24 of 196, 12.2%), PIK3CA mutations (15 of 114, 13.2%), KRAS and PIK3CA mutations (9 of 114, 7.9%), low PTEN expression (97 of 183, 53.0%), and high pMET expression (38 of 64, 59.4%). In total, 68 patients received 82 different MTAs: phosphoinositide 3-kinase (PI3K) pathway inhibitor (if PIK3CA mutation, n ¼ 10; or low PTEN, n ¼ 32), PI3K pathway inhibitor plus MEK inhibitor (if KRAS mutation, n ¼ 10; or BRAF mutation, n ¼ 1), second-generation anti-EGF receptor monoclonal antibodies (if wild-type KRAS, n ¼ 11), anti-hepatocyte growth factor monoclonal antibody (if high pMET, n ¼ 10), mTOR inhibitor plus anti-insulin-like growth factor-1 receptor monoclonal antibody (if low PTEN, n ¼ 5), and BRAF inhibitor (if BRAF mutation, n ¼ 3). Median time-to-treatment failure on MTA was 7.9 versus 16.3 weeks for their prior systemic antitumor therapy (P < 0.001). Partial response was seen in 1 patient [1.2%, PI3K inhibitor with PIK3CA mutation] and stable disease >16 weeks in 10 cases (12.2%). These results suggest that matching chemorefractory patients with colorectal cancer with targeted agents in phase I trials based on the current molecular profile does not confer a significant clinical benefit. Mol Cancer Ther; 11(9); 2062-71. Ó2012 AACR.

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Section: Discussionsupporting

confidence: 75%

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

Dienstmann

Serpico

Rodón

et al. 2012

Molecular Cancer Therapeutics

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“…Therefore, targeting the proteasome may represent a valuable alternative to BRAF or MEK kinase inhibition for the treatment of BRAF-mutant tumors harboring PTEN or RB1 alterations. BRAF inhibitors showed poor activity also in BRAF mutated metastatic colorectal cancer (17,29), and novel treatment strategies are required to improve treatment options and survival in such patients.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with metastatic colorectal cancer with BRAF-mutant tumors have a poor prognosis and do not respond to BRAF inhibitors in monotherapy (16,17). Accordingly, the development of therapeutic strategies for metastatic BRAF mutated colorectal cancer represent an urgent and unmet clinical need.…”

Section: Introductionmentioning

confidence: 99%

BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors

Zecchin

Boscaro

Medico

et al. 2013

Molecular Cancer Therapeutics

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A critical step toward defining tailored therapy in patients with cancer is the identification of genetic interactions that may impair-or boost-the efficacy of selected therapeutic approaches. Cell models able to recapitulate combinations of genetic aberrations are important to find drug-genotype interactions poorly affected by the heterogeneous genetics of human tumors. In order to identify novel pharmacogenomic relationships, we employed an isogenic cell panel that reconstructs cancer genetic scenarios. We screened a library of 43 compounds in human hTERT-HME1 epithelial cells in which PTEN or RB1 were silenced in combination with the targeted knockin of cancer-associated mutations in EGFR, KRAS, BRAF, or PIK3CA oncogenes. Statistical analysis and clustering algorithms were applied to display similar drug response profiles and mutation-specific patterns of activity. From the screen, we discovered that proteasome inhibitors show selectivity toward BRAF V600E-mutant cells, irrespective of PTEN or RB1 expression. Preferential targeting of BRAF-mutant cells by proteasome inhibitors was corroborated in a second BRAF V600E isogenic model, as well as in a panel of colorectal cancer cell lines by the use of the proteasome inhibitor carfilzomib. Notably, carfilzomib also showed striking in vivo activity in a BRAF-mutant human colorectal cancer xenograft model. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Our findings indicated that proteasome inhibition might represent a valuable targeting strategy in BRAF V600E-mutant colorectal tumors. Mol Cancer Ther; 12(12); 2950-61. Ó2013 AACR.

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“…This is particularly important as B mutant patients have questionable benefit from antiBepidermal growth factor receptor (antiBEGFR) therapies [6] and Btargeted strategies have yet to make clinical impact in aCRC. [7,8] Importantly previous publications have not performed careful multivariate analysis. This is critical as Bmutant aCRC is associated with clinicopathological features which are themselves negative prognostic factors, [9] including defective mismatch repair (dMMR) status [4,10] , right sided primary tumour location (PTL) [11] and a high incidence of peritoneal metastases.…”

Section: Introductionmentioning

confidence: 99%