Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAF

Feng, Xing; Persaud, Yogindra; Pratilas, Christine A.; Taylor, Barry S.; Janakiraman, Manickam; She, Qing‐Bai; Gallardo, Humilidad F.; Liu, C.; Merghoub, Taha; Hefter, Blake; Dolgalev, Igor; Viale, Agnès; Heguy, Adriana; Stanchina, Elisa de; Cobrinik, David; Bollag, Gideon; Wolchok, Jedd D.; Houghton, Alan N.; Solit, David B.

doi:10.1038/onc.2011.250

Cited by 180 publications

(162 citation statements)

References 39 publications

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“…The hotspot RAC P29S mutation also confers resistance to RAF and MEK inhibitors 26 . Mutations affecting p16 INK4a were also found at baseline and inactivation of this tumour suppressor was associated with a shorter PFS in patients treated with dabrafenib 43 44,45 .…”

Section: Discussionmentioning

confidence: 99%

Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

et al. 2014

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One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF V600 -mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2 C125S , but not the synonymous MEK1 C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.

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Section: Discussionmentioning

confidence: 99%

Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

et al. 2014

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“…Selective as concomitant mutational inactivation of PTEN or RB1 diminished response to those agents in melanomas harboring BRAF V600E (37). 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.…”

Section: Discussionmentioning

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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“…Ganetespib potently reduced cell viability in all lines examined, with IC 50 values in the low nanomolar range. Interestingly A2058 cells, which have lost their dependence on BRAF V600E due to inactivation of PTEN and RB1 (19), remained acutely sensitive to ganetespib exposure. Next, we examined expression changes in client and signaling pathway proteins using the A375 melanoma line.…”

Section: Loss Of Viability and Oncogenic Signaling By Ganetespib In Bmentioning

confidence: 99%

“…1D; ref. 19). Caspase-3/7 activity was quantified in A375 cells following inhibitor treatment as a measure of apoptotic induction (Fig.…”

Section: Loss Of Viability and Oncogenic Signaling By Ganetespib In Bmentioning

confidence: 99%

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

Acquaviva

Smith

Jimenez

et al. 2014

Molecular Cancer Therapeutics

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Activating BRAF kinase mutations serve as oncogenic drivers in over half of all melanomas, a feature that has been exploited in the development of new molecularly targeted approaches to treat this disease. Selective BRAF V600E inhibitors, such as vemurafenib, typically induce initial, profound tumor regressions within this group of patients; however, durable responses have been hampered by the emergence of drug resistance. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90, in melanoma lines harboring the BRAF V600E mutation. Ganetespib exposure resulted in the loss of mutant BRAF expression and depletion of mitogen-activated protein kinase and AKT signaling, resulting in greater in vitro potency and antitumor efficacy compared with targeted BRAF and MAP-ERK kinase (MEK) inhibitors. Dual targeting of Hsp90 and BRAF V600E provided combinatorial benefit in vemurafenibsensitive melanoma cells in vitro and in vivo. Importantly, ganetespib overcame mechanisms of intrinsic and acquired resistance to vemurafenib, the latter of which was characterized by reactivation of extracellular signal-regulated kinase (ERK) signaling. Continued suppression of BRAF V600E by vemurafenib potentiated sensitivity to MEK inhibitors after acquired resistance had been established. Ganetespib treatment reduced, but not abolished, elevations in steady-state ERK activity. Profiling studies revealed that the addition of a MEK inhibitor could completely abrogate ERK reactivation in the resistant phenotype, with ganetespib displaying superior combinatorial activity over vemurafenib. Moreover, ganetespib plus the MEK inhibitor TAK-733 induced tumor regressions in vemurafenib-resistant xenografts. Overall these data highlight the potential of ganetespib as a single-agent or combination treatment in BRAF V600E -driven melanoma, particularly as a strategy to overcome acquired resistance to selective BRAF inhibitors. Mol Cancer Ther; 13(2); 353-63. Ó2014 AACR.

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Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring V600EBRAF

Cited by 180 publications

References 39 publications

Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

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