Nras in melanoma: Targeting the undruggable target

Mandalà, Mario; Merelli, Barbara; Massi, Daniela

doi:10.1016/j.critrevonc.2014.05.005

Cited by 61 publications

(72 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With regards to NRAS, the most common oncogenic change (80-90% of all NRAS mutations) reported is a point mutation at position 61, with mutations at positions 12 and 13 occurring less frequently. 4 In the largest single-institution cohort of melanoma patients characterized for activating BRAF and NRAS mutations, the most common NRAS mutation was represented by the glutamine to arginine substitution at position 61 (NRASQ61R). 5 NRAS has so far proven to be intractable to conventional drug discovery, and several different strategies of directly targeting RAS have not resulted in effective therapeutics.…”

mentioning

confidence: 99%

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

Self Cite

View full text Add to dashboard Cite

Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.

show abstract

mentioning

confidence: 99%

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…13 This specific structure causes difficulties in targeting; hence, RAS was named the "undruggable" target. 13 RAS mutations are found in around 30% of melanomas and usually affect NRAS (Q61R, Q61K, and Q61H). 7,11,14 RAS not only activates the MAPK pathway, but also has activators and effectors among other cellular pathways such as phosphatidylinositol-3 kinases (PI3K), T-Cell Lymphoma Invasion and Metastasis 1 (TIAM1) and others.…”

Section: Genetic Landscape Of Mutationsmentioning

confidence: 99%

“…7,11,14 RAS not only activates the MAPK pathway, but also has activators and effectors among other cellular pathways such as phosphatidylinositol-3 kinases (PI3K), T-Cell Lymphoma Invasion and Metastasis 1 (TIAM1) and others. 13 The third most frequently identified genetic mutation is located in the NF1 tumor suppressor gene, which serves as a regulator of RAS through GTP-ase activating protein.…”

Section: Genetic Landscape Of Mutationsmentioning

confidence: 99%

“…Mutations in the RAS gene impair inactivation and keep RAS protein in the activated state. 13 The active form, RAS-GTP, initiates phosphorylation of RAF and subsequently MEK and ERK and leads to the activation of the MAPK pathway. 13 This specific structure causes difficulties in targeting; hence, RAS was named the "undruggable" target.…”

Section: Genetic Landscape Of Mutationsmentioning

confidence: 99%

“…13 The active form, RAS-GTP, initiates phosphorylation of RAF and subsequently MEK and ERK and leads to the activation of the MAPK pathway. 13 This specific structure causes difficulties in targeting; hence, RAS was named the "undruggable" target. 13 RAS mutations are found in around 30% of melanomas and usually affect NRAS (Q61R, Q61K, and Q61H).…”

Section: Genetic Landscape Of Mutationsmentioning

confidence: 99%

See 2 more Smart Citations

Developments in targeted therapy in melanoma

Amann

Ramelyte

Thurneysen

et al. 2017

European Journal of Surgical Oncology (EJSO)

View full text Add to dashboard Cite

Melanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations). The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent longterm outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy. AbstractMelanomas are disease entities driven in part by the mitogen activated protein kinase (MAPK) pathway. The TCGA network recently defined four genetic subtypes based on the most prevalent significantly mutated genes, including mutant BRAF, mutant RAS (N/H/K), mutant NF1, and Triple wild-type melanoma (harboring none of the aforementioned mutations, but instead includes KIT, GNA and GNAQ mutations).The successful development of kinase inhibitors marked a milestone in the treatment of metastatic melanoma. Combination treatment with a BRAF-and MEK-inhibitor is the current standard of care for inoperable stage IIIC/IV BRAF-mutated melanoma. Recent data demonstrate excellent long-term outcome, especially in patients with normal baseline LDH levels, and confirm that there is a subset of BRAF inhibitor-naive patients who experience durable responses without progression on combination treatment. In the future, adding a third compound based on individual genetic alterations might further improve the outcome of targeted therapy.

show abstract

Association BetweenNRASandBRAFMutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma

et al. 2015

View full text Add to dashboard Cite

Importance NRAS and BRAF mutations in melanoma inform current treatment paradigms but their role in survival from primary melanoma has not been established. Identification of patients at high risk of melanoma-related death based on their primary melanoma characteristics before evidence of recurrence could inform recommendations for patient follow-up and eligibility for adjuvant trials. Objective To determine tumor characteristics and survival from primary melanoma by somatic NRAS and BRAF status. Design, Setting, and Participants A population-based study with median follow-up of 7.6 years for 912 patients with first primary cutaneous melanoma analyzed for NRAS and BRAF mutations diagnosed in the year 2000 from the United States and Australia in the Genes, Environment and Melanoma Study and followed through 2007. Main Outcomes and Measures Tumor characteristics and melanoma-specific survival of primary melanoma by NRAS and BRAF mutational status. Results The melanomas were 13% NRAS+, 30% BRAF+, and 57% with neither NRAS nor BRAF mutation (wildtype). In a multivariable model including clinicopathologic characteristics, NRAS+ melanoma was associated (P<.05) with mitoses, lower tumor infiltrating lymphocyte (TIL) grade, and anatomic site other than scalp/neck and BRAF+ melanoma was associated with younger age, superficial spreading subtype, and mitoses, relative to wildtype melanoma. There was no significant difference in melanoma-specific survival for melanoma harboring mutations in NRAS (HR 1.7, 95% CI, 0.8–3.4) or BRAF (HR, 1.5, 95% CI, 0.8–2.9) compared to wildtype melanoma adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. However, melanoma-specific survival was significantly poorer for higher risk (T2b or higher stage) tumors with NRAS (HR 2.9; 95% CI 1.1–7.7) or BRAF (HR 3.1; 95% CI 1.2–8.5) mutations but not for lower risk (T2a or lower) tumors (P=.65) adjusted for age, sex, site, AJCC tumor stage, TIL grade, and study center. Conclusions and Relevance Lower TIL grade for NRAS+ melanoma suggests it has a more immunosuppressed microenvironment, which may impact its response to immunotherapies. Further, the approximately three-fold increased death rate for higher risk tumors harboring NRAS or BRAF mutations compared to wildtype melanomas after adjusting for other prognostic factors indicates that the prognostic implication of NRAS and BRAF mutations deserves further investigation, particularly in higher AJCC stage primary melanomas.

show abstract

Nras in melanoma: Targeting the undruggable target

Cited by 61 publications

References 96 publications

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Immunohistochemistry is highly sensitive and specific for the detection of NRASQ61R mutation in melanoma

Developments in targeted therapy in melanoma

Association BetweenNRASandBRAFMutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma

Contact Info

Product

Resources

About