RAS and MYC rank amongst the most commonly altered oncogenes in cancer,with RAS being the most frequently mutated and MYC the most amplified.The cooperative interplay between RAS and MYC constitutes a complex and mult...RAS and MYC rank amongst the most commonly altered oncogenes in cancer,with RAS being the most frequently mutated and MYC the most amplified.The cooperative interplay between RAS and MYC constitutes a complex and multifaceted phenomenon,profoundly influencing tumor development.Together and individually,these two oncogenes regulate most,if not all,hallmarks of cancer,including cell death escape,replicative immortality,tumor-associated angiogenesis,cell invasion and metastasis,metabolic adaptation,and immune evasion.Due to their frequent alteration and role in tumorigenesis,MYC and RAS emerge as highly appealing targets in cancer therapy.However,due to their complex nature,both oncogenes have been long considered“undruggable”and,until recently,no drugs directly targeting them had reached the clinic.This review aims to shed light on their complex partnership,with special attention to their active collaboration in fostering an immunosuppressive milieu and driving immunotherapeutic resistance in cancer.Within this review,we also present an update on the different inhibitors targeting RAS and MYC currently undergoing clinical trials,along with their clinical outcomes and the different combination strategies being explored to overcome drug resistance.This recent clinical development suggests a paradigm shift in the long-standing belief of RAS and MYC“undruggability”,hinting at a new era in their therapeutic targeting.展开更多
The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified.Since then,over 40 years of unceasing research have hi...The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified.Since then,over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation,especially in hematologic diseases.Indeed,some of the earliest connections among the higher expression of proto-oncogenes(such as MYC),genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma,chronic myeloid leukemia and mouse plasmacytomas.Multiple myeloma(MM),in particular,is a plasma cell malignancy strictly associated with MYC deregulation,suggesting that therapeutic strategies against it would be beneficial in treating this disease.However,targeting MYC was-and,somehow,still is-challenging due to its unique properties:lack of defined three-dimensional structure,nuclear localization and absence of a targetable enzymatic pocket.Despite these difficulties,however,many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition.Different molecules have been tested,in fact,in the context of MM.In this review,we summarize the current status of the different compounds,including the results of their clinical testing,and propose to continue with the efforts to identify,repurpose,redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.展开更多
MYC plays a central role in tumorigenesis by orchestrating cell proliferation,growth and survival,among other transformation mechanisms.In particular,MYC has often been associated with lymphomagenesis.In fact,MYC over...MYC plays a central role in tumorigenesis by orchestrating cell proliferation,growth and survival,among other transformation mechanisms.In particular,MYC has often been associated with lymphomagenesis.In fact,MYC overexpressing lymphomas such as high-grade B-cell lymphoma(HGBL)and double expressor diffuse large B-cell lymphomas(DLBCL),are considered addicted to MYC.In such a context,MYC targeting therapies are of special interest,as MYC withdrawal is expected to result in tumor regression.However,whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet.Even though no MYC inhibitor has received regulatory approval to date,substantial efforts have been made to investigate avenues to render MYC a druggable target.Here,we summarize the different classes of molecules currently under development,which mostly target MYC indirectly in aggressive B-cell lymphomas,paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.展开更多
基金funding support by the“Proyectos de I+D+i en Líneas Estratégicas”(PLEC2021-007959)grant from the Spanish Ministry of Economy and CompetitivenessLa MaratóTV3 grant(2019429)+4 种基金the Spanish Ministry of Science and Innovation and European Union through the NextGenerationEU program,in the context of the Plan de Recuperacion,Transformacion y Resiliencia(RETOSCPP2022-009808)a European Research Council(ERC)Advanced Grant(101142260)the 2nd BBVA Foundation Comprehensive Program of Cancer Immunotherapy&Immunology(CAIMI-II)grant.I.G.-L.was supported by a grant from the University Teacher Training Program(FPU),Ministry of Universities(FPU20/04812)Authors from VHIO acknowledge the State Agency for Research(Agencia Estatal de Investigación)the financial support as a Center of Excellence Severo Ochoa(CEX2020-001024-S/AEI/10.13039/501100011033).
文摘RAS and MYC rank amongst the most commonly altered oncogenes in cancer,with RAS being the most frequently mutated and MYC the most amplified.The cooperative interplay between RAS and MYC constitutes a complex and multifaceted phenomenon,profoundly influencing tumor development.Together and individually,these two oncogenes regulate most,if not all,hallmarks of cancer,including cell death escape,replicative immortality,tumor-associated angiogenesis,cell invasion and metastasis,metabolic adaptation,and immune evasion.Due to their frequent alteration and role in tumorigenesis,MYC and RAS emerge as highly appealing targets in cancer therapy.However,due to their complex nature,both oncogenes have been long considered“undruggable”and,until recently,no drugs directly targeting them had reached the clinic.This review aims to shed light on their complex partnership,with special attention to their active collaboration in fostering an immunosuppressive milieu and driving immunotherapeutic resistance in cancer.Within this review,we also present an update on the different inhibitors targeting RAS and MYC currently undergoing clinical trials,along with their clinical outcomes and the different combination strategies being explored to overcome drug resistance.This recent clinical development suggests a paradigm shift in the long-standing belief of RAS and MYC“undruggability”,hinting at a new era in their therapeutic targeting.
文摘The importance of MYC function in cancer was discovered in the late 1970s when the sequence of the avian retrovirus that causes myelocytic leukemia was identified.Since then,over 40 years of unceasing research have highlighted the significance of this protein in malignant transformation,especially in hematologic diseases.Indeed,some of the earliest connections among the higher expression of proto-oncogenes(such as MYC),genetic rearrangements and their relation to cancer development were made in Burkitt lymphoma,chronic myeloid leukemia and mouse plasmacytomas.Multiple myeloma(MM),in particular,is a plasma cell malignancy strictly associated with MYC deregulation,suggesting that therapeutic strategies against it would be beneficial in treating this disease.However,targeting MYC was-and,somehow,still is-challenging due to its unique properties:lack of defined three-dimensional structure,nuclear localization and absence of a targetable enzymatic pocket.Despite these difficulties,however,many studies have shown the potential therapeutic impact of direct or indirect MYC inhibition.Different molecules have been tested,in fact,in the context of MM.In this review,we summarize the current status of the different compounds,including the results of their clinical testing,and propose to continue with the efforts to identify,repurpose,redesign or improve drug candidates to combine them with standard of care therapies to overcome resistance and enable better management of myeloma treatment.
文摘MYC plays a central role in tumorigenesis by orchestrating cell proliferation,growth and survival,among other transformation mechanisms.In particular,MYC has often been associated with lymphomagenesis.In fact,MYC overexpressing lymphomas such as high-grade B-cell lymphoma(HGBL)and double expressor diffuse large B-cell lymphomas(DLBCL),are considered addicted to MYC.In such a context,MYC targeting therapies are of special interest,as MYC withdrawal is expected to result in tumor regression.However,whether high MYC levels are always predictive of increased sensitivity to these approaches is not clear yet.Even though no MYC inhibitor has received regulatory approval to date,substantial efforts have been made to investigate avenues to render MYC a druggable target.Here,we summarize the different classes of molecules currently under development,which mostly target MYC indirectly in aggressive B-cell lymphomas,paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.
