{"id":"https://openalex.org/W13524344","doi":null,"title":"Primary resistance to ATP-competitive mTOR inhibitors for the treatment of solid tumors","display_name":"Primary resistance to ATP-competitive mTOR inhibitors for the treatment of solid tumors","publication_year":2013,"publication_date":"2013-01-01","ids":{"openalex":"https://openalex.org/W13524344","mag":"13524344"},"language":"en","primary_location":{"id":"pmh:oai:escholarship.org/ark:/13030/qt2vw456fk","doi":null,"is_oa":true,"landing_page_url":"https://escholarship.org/uc/item/2vw456fk","pdf_url":"https://escholarship.org/uc/item/2vw456fk","source":{"id":"https://openalex.org/S4306400115","display_name":"eScholarship (California Digital Library)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2801248553","host_organization_name":"California Digital Library","host_organization_lineage":["https://openalex.org/I2801248553"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"","raw_type":"etd"},"volume":null,"type":"dissertation","is_traditional":true,"indexed_in":[],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://escholarship.org/uc/item/2vw456fk","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5081915409","display_name":"Gregory S. Ducker","orcid":"https://orcid.org/0000-0002-8651-6846","observed_orcids":["https://orcid.org/0000-0002-8651-6846"]},"institutions":[],"countries":[],"is_corresponding":true,"raw_author_name":"Gregory S. Ducker","raw_affiliation_strings":[],"raw_orcid":"https://orcid.org/0000-0002-8651-6846","affiliations":[]}],"institutions":[],"countries_distinct_count":0,"institutions_distinct_count":0,"corresponding_author_ids":["https://openalex.org/A5081915409"],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10952","display_name":"PI3K/AKT/mTOR signaling in cancer","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T10952","display_name":"PI3K/AKT/mTOR signaling in cancer","score":1.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T12829","display_name":"Advanced Breast Cancer Therapies","score":0.0,"subfield":{"id":"https://openalex.org/subfields/2730","display_name":"Oncology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T11339","display_name":"Metabolism, Diabetes, and Cancer","score":0.0,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/mtor-inhibitors","display_name":"mTOR inhibitors","score":0.9300000071525574},{"id":"https://openalex.org/keywords/atp-competitive-inhibitors","display_name":"ATP-competitive inhibitors","score":0.7979999780654907},{"id":"https://openalex.org/keywords/pp242","display_name":"PP242","score":0.9279999732971191},{"id":"https://openalex.org/keywords/mln0128","display_name":"MLN0128","score":0.9869999885559082},{"id":"https://openalex.org/keywords/rapamycin","display_name":"rapamycin","score":0.8730000257492065},{"id":"https://openalex.org/keywords/drug-resistance","display_name":"drug resistance","score":0.8109999895095825},{"id":"https://openalex.org/keywords/pik3ca-mutation","display_name":"PIK3CA mutation","score":0.878000020980835},{"id":"https://openalex.org/keywords/colon-cancer","display_name":"colon cancer","score":0.7120000123977661}],"concepts":[{"id":"https://openalex.org/C86554907","wikidata":"https://www.wikidata.org/wiki/Q285613","display_name":"PI3K/AKT/mTOR pathway","level":3,"score":0.9127593636512756},{"id":"https://openalex.org/C43060935","wikidata":"https://www.wikidata.org/wiki/Q18043110","display_name":"RPTOR","level":4,"score":0.622749924659729},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.5752464532852173},{"id":"https://openalex.org/C502942594","wikidata":"https://www.wikidata.org/wiki/Q3421914","display_name":"Cancer research","level":1,"score":0.5353773832321167},{"id":"https://openalex.org/C184235292","wikidata":"https://www.wikidata.org/wiki/Q421851","display_name":"Kinase","level":2,"score":0.5182335376739502},{"id":"https://openalex.org/C2777949483","wikidata":"https://www.wikidata.org/wiki/Q285613","display_name":"Mechanistic target of rapamycin","level":4,"score":0.5160179138183594},{"id":"https://openalex.org/C107846503","wikidata":"https://www.wikidata.org/wiki/Q14876061","display_name":"mTORC2","level":5,"score":0.49840760231018066},{"id":"https://openalex.org/C121608353","wikidata":"https://www.wikidata.org/wiki/Q12078","display_name":"Cancer","level":2,"score":0.4139552712440491},{"id":"https://openalex.org/C62478195","wikidata":"https://www.wikidata.org/wiki/Q828130","display_name":"Signal transduction","level":2,"score":0.3848913908004761},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.37861526012420654},{"id":"https://openalex.org/C98490376","wikidata":"https://www.wikidata.org/wiki/Q14876060","display_name":"mTORC1","level":4,"score":0.2625841498374939},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.16856685280799866}],"mesh":[],"locations_count":3,"locations":[{"id":"pmh:oai:escholarship.org/ark:/13030/qt2vw456fk","doi":null,"is_oa":true,"landing_page_url":"https://escholarship.org/uc/item/2vw456fk","pdf_url":"https://escholarship.org/uc/item/2vw456fk","source":{"id":"https://openalex.org/S4306400115","display_name":"eScholarship (California Digital Library)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2801248553","host_organization_name":"California Digital Library","host_organization_lineage":["https://openalex.org/I2801248553"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"","raw_type":"etd"},{"id":"pmh:qt2vw456fk","doi":null,"is_oa":true,"landing_page_url":"http://www.escholarship.org/uc/item/2vw456fk","pdf_url":"http://www.escholarship.org/uc/item/2vw456fk","source":{"id":"https://openalex.org/S4306400115","display_name":"eScholarship (California Digital Library)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2801248553","host_organization_name":"California Digital Library","host_organization_lineage":["https://openalex.org/I2801248553"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"Ducker, Gregory Stuart. (2013). Primary resistance to ATP-competitive mTOR inhibitors for the treatment of solid tumors. UC Berkeley: Chemistry. Retrieved from: http://www.escholarship.org/uc/item/2vw456fk","raw_type":"dissertation"},{"id":"mag:13524344","doi":null,"is_oa":false,"landing_page_url":"https://escholarship.org/content/qt2vw456fk/qt2vw456fk.pdf?t=mtfdi6","pdf_url":null,"source":null,"license":null,"license_id":null,"version":null,"is_accepted":false,"is_published":false,"raw_source_name":null,"raw_type":null}],"best_oa_location":{"id":"pmh:oai:escholarship.org/ark:/13030/qt2vw456fk","doi":null,"is_oa":true,"landing_page_url":"https://escholarship.org/uc/item/2vw456fk","pdf_url":"https://escholarship.org/uc/item/2vw456fk","source":{"id":"https://openalex.org/S4306400115","display_name":"eScholarship (California Digital Library)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2801248553","host_organization_name":"California Digital Library","host_organization_lineage":["https://openalex.org/I2801248553"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"submittedVersion","is_accepted":false,"is_published":false,"raw_source_name":"","raw_type":"etd"},"sustainable_development_goals":[{"display_name":"Good health and well-being","score":0.9537000060081482,"id":"https://metadata.un.org/sdg/3"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"pdf":true,"grobid_xml":true},"content_urls":{"pdf":"https://content.openalex.org/works/W13524344.pdf","grobid_xml":"https://content.openalex.org/works/W13524344.grobid-xml"},"referenced_works_count":129,"referenced_works":["https://openalex.org/W1569327468","https://openalex.org/W1587094587","https://openalex.org/W1596556260","https://openalex.org/W1852153956","https://openalex.org/W1918384196","https://openalex.org/W1965626427","https://openalex.org/W1968852924","https://openalex.org/W1969292035","https://openalex.org/W1971791161","https://openalex.org/W1974584534","https://openalex.org/W1976896999","https://openalex.org/W1976979132","https://openalex.org/W1978194521","https://openalex.org/W1980396381","https://openalex.org/W1981421409","https://openalex.org/W1982219839","https://openalex.org/W1982972087","https://openalex.org/W1983698019","https://openalex.org/W1984621921","https://openalex.org/W1987443121","https://openalex.org/W1988303870","https://openalex.org/W1991613093","https://openalex.org/W1992170852","https://openalex.org/W1992257057","https://openalex.org/W1995496043","https://openalex.org/W1999433592","https://openalex.org/W2000954296","https://openalex.org/W2002226709","https://openalex.org/W2004688803","https://openalex.org/W2005346481","https://openalex.org/W2006559495","https://openalex.org/W2007110714","https://openalex.org/W2008345619","https://openalex.org/W2010685617","https://openalex.org/W2010922894","https://openalex.org/W2011474502","https://openalex.org/W2012346684","https://openalex.org/W2015866661","https://openalex.org/W2015973524","https://openalex.org/W2021012077","https://openalex.org/W2022609682","https://openalex.org/W2023012828","https://openalex.org/W2024114074","https://openalex.org/W2024839583","https://openalex.org/W2027785297","https://openalex.org/W2033338515","https://openalex.org/W2034412853","https://openalex.org/W2035495486","https://openalex.org/W2035521247","https://openalex.org/W2035971989","https://openalex.org/W2037831873","https://openalex.org/W2043398720","https://openalex.org/W2050980183","https://openalex.org/W2051651213","https://openalex.org/W2052326711","https://openalex.org/W2053874502","https://openalex.org/W2057106513","https://openalex.org/W2058843172","https://openalex.org/W2059975503","https://openalex.org/W2062573083","https://openalex.org/W2065887259","https://openalex.org/W2067168610","https://openalex.org/W2070732456","https://openalex.org/W2071734901","https://openalex.org/W2072236227","https://openalex.org/W2077804275","https://openalex.org/W2081920342","https://openalex.org/W2084875329","https://openalex.org/W2085483616","https://openalex.org/W2086338749","https://openalex.org/W2093431913","https://openalex.org/W2095692554","https://openalex.org/W2098912234","https://openalex.org/W2101083009","https://openalex.org/W2101815035","https://openalex.org/W2101885674","https://openalex.org/W2102677587","https://openalex.org/W2103445331","https://openalex.org/W2103894337","https://openalex.org/W2104830962","https://openalex.org/W2111607026","https://openalex.org/W2112064092","https://openalex.org/W2113432343","https://openalex.org/W2114869204","https://openalex.org/W2115504370","https://openalex.org/W2115655607","https://openalex.org/W2116622644","https://openalex.org/W2117022661","https://openalex.org/W2117692326","https://openalex.org/W2118677643","https://openalex.org/W2120490763","https://openalex.org/W2122147796","https://openalex.org/W2124225877","https://openalex.org/W2124593509","https://openalex.org/W2126783165","https://openalex.org/W2127063807","https://openalex.org/W2128059625","https://openalex.org/W2128542677","https://openalex.org/W2131218123","https://openalex.org/W2132948440","https://openalex.org/W2137083986","https://openalex.org/W2138871725","https://openalex.org/W2141424872","https://openalex.org/W2144323242","https://openalex.org/W2145719260","https://openalex.org/W2148933046","https://openalex.org/W2149229980","https://openalex.org/W2150575159","https://openalex.org/W2151089236","https://openalex.org/W2152289580","https://openalex.org/W2152600551","https://openalex.org/W2153867442","https://openalex.org/W2154515817","https://openalex.org/W2154836325","https://openalex.org/W2156144699","https://openalex.org/W2159187753","https://openalex.org/W2160079255","https://openalex.org/W2160982674","https://openalex.org/W2162647235","https://openalex.org/W2164452916","https://openalex.org/W2166587097","https://openalex.org/W2166721860","https://openalex.org/W2167188058","https://openalex.org/W2168180694","https://openalex.org/W2170137742","https://openalex.org/W2172077519","https://openalex.org/W2262414037","https://openalex.org/W2273740586","https://openalex.org/W2413355317"],"related_works":["https://openalex.org/W2029348880","https://openalex.org/W2954917865","https://openalex.org/W2388363223","https://openalex.org/W2066035892","https://openalex.org/W2168298851","https://openalex.org/W1980352382","https://openalex.org/W2039713818","https://openalex.org/W1988338260","https://openalex.org/W4230213610","https://openalex.org/W2054117275"],"abstract_inverted_index":{"The":[0,164,608,755],"mammalian":[1],"target":[2,142],"of":[3,45,54,71,85,98,122,147,167,177,182,190,226,235,246,253,258,338,416,435,439,457,497,514,524,533,563,575,634,709,727,738,758,768,797],"rapamycin":[4,285],"(mTOR)":[5],"functions":[6],"to":[7,18,34,118,170,199,295,306,327,341,346,357,364,382,403,464,470,490,494,544,588,600,604,673,689,693,701,703,715,733,741],"integrate":[8],"nutrient":[9],"and":[10,25,36,56,87,109,115,157,179,185,224,248,270,286,317,362,390,433,441,453,521,546,565,567,585,597,637,658,721,787],"energy":[11],"availability":[12],"with":[13,132,215,401,511,551,699],"extracellular":[14],"growth":[15,80],"factor":[16,81],"signals":[17],"regulate":[19],"macromolecular":[20],"biosynthesis":[21],"including":[22],"protein":[23,528],"translation":[24,64],"lipogenesis.":[26],"This":[27,302,736],"essential":[28],"gene":[29,411],"in":[30,63,76,93,151,208,315,409,472,516,577,622,663,680,725,744,774,795],"conserved":[31,149],"from":[32,616],"yeast":[33],"humans":[35],"is":[37,47,101,111,213,312,549,619,780],"a":[38,48,52,130,133,242,351,366,386,414,467,491,568,590,632,638,667,707,723,781],"core":[39],"metabolic":[40,162],"regulatory":[41],"element.":[42],"Aberrant":[43],"regulation":[44],"metabolism":[46],"phenotype":[49],"recognized":[50],"as":[51,196,202,204,287,323,730,751,753,769],"hallmark":[53],"cancer,":[55,348],"it":[57,311,425,599],"has":[58,330,370],"been":[59,230,262,332,371],"shown":[60],"that":[61,120,264,369,483,570,618,712],"increases":[62],"alone":[65],"can":[66,536,628,641],"be":[67,126,304,629,642,742,789],"oncogenic.":[68],"Additionally,":[69],"many":[70,94,153,276,664],"the":[72,79,175,220,233,251,266,336,374,410,427,475,498,512,517,547,649,674,716],"most":[73],"common":[74,743],"oncogenes":[75],"cancer":[77,108,316,423,447,459,479,542,556,592,614,651,748],"alter":[78],"signaling":[82,124,662,777],"network":[83],"upstream":[84],"mTOR":[86,92,99,123,138,168,200,212,240,259,309,328,344,429,440,505,576,661,718,760],"these":[88,606,798],"lesions":[89,156,193,320],"likely":[90],"activate":[91],"cancers.":[95],"Thus,":[96],"repression":[97],"activity":[100],"an":[102,140,188,645,765],"emerging":[103],"therapeutic":[104,144,298],"strategy":[105],"for":[106,143,161,207,232,308,360,784,792],"human":[107,347],"there":[110],"both":[112,404],"strong":[113],"mechanistic":[114],"epidemiological":[116],"evidence":[117],"suggest":[119],"attenuation":[121],"may":[125,303],"broadly":[127],"applicable.":[128],"As":[129],"kinase":[131,184,267,529,776],"defined":[134],"small-molecule":[135],"binding":[136],"pocket,":[137],"presents":[139],"attractive":[141],"intervention":[145],"because":[146,310,424],"its":[148,158],"role":[150],"integrating":[152],"different":[154],"oncogenic":[155,192],"central":[159],"requirement":[160],"regulation.":[163],"successful":[165],"application":[166],"inhibitors":[169,181,257,329,345,444],"clinical":[171,290,377,793],"oncology":[172],"will":[173],"require":[174],"development":[176],"potent":[178,283],"selective":[180],"this":[183,227,484,734,775],"equally":[186],"importantly,":[187],"understanding":[189],"which":[191],"mark":[194,321],"tumors":[195,686],"specifically":[197],"sensitive":[198],"inhibition":[201,574,726,757],"well":[203,582,752],"independent":[205,523],"biomarkers":[206],"vivo":[209],"efficacy.":[210],"Fortuitously,":[211],"inhibited":[214,660],"near":[216],"perfect":[217],"selectivity":[218],"by":[219,462],"natural":[221],"product":[222],"rapamycin,":[223,383],"analogs":[225],"compound":[228,368,389],"have":[229,260,581],"approved":[231],"treatment":[234],"solid":[236],"tumors.":[237,665],"Rapamycin":[238],"inhibits":[239],"through":[241],"non-conserved":[243],"non-competitive":[244],"mechanism":[245,548,737],"action":[247],"only":[249],"blocks":[250],"phosphorylation":[252,496,697,729],"certain":[254],"substrates.":[255],"ATP-competitive":[256,343,717,785],"recently":[261],"invented":[263],"occupy":[265],"active":[268,518],"site":[269],"block":[271],"all":[272],"substrate":[273],"phosphorylation.":[274,553],"In":[275,380,554,648,666],"preclinical":[277],"models":[278],"they":[279,288],"are":[280],"significantly":[281,399],"more":[282,387,391],"than":[284],"enter":[289],"trials,":[291],"questions":[292],"about":[293],"how":[294,339],"maximize":[296],"their":[297],"index":[299],"naturally":[300],"arise.":[301],"challenging":[305],"ask":[307],"not":[313,326,331],"mutated":[314],"what":[318,677],"genetic":[319],"cancers":[322],"susceptible":[324],"or":[325],"determined.":[333],"To":[334],"address":[335],"question":[337],"best":[340],"apply":[342,598],"I":[349,376,418,481,559,586,705,762],"performed":[350],"large":[352],"(~650)":[353],"unbiased":[354],"cell":[355,392,448,460,557,681,710,749],"screen":[356],"identify":[358],"markers":[359,562],"sensitivity":[361,463,564,672],"resistance":[363,402,469,487,566,739],"PP242,":[365,407],"tool":[367],"developed":[372],"into":[373,631],"phase":[375],"drug,":[378],"MLN0128.":[379],"comparison":[381],"PP242":[384,465,545,654,720],"was":[385,398,488,522,655,678],"effective":[388],"lines":[393,449,461,558,580,711,750],"were":[394,413,507,687,713],"inhibited.":[395,508],"Colon":[396],"origin":[397],"associated":[400],"drugs.":[405],"For":[406],"mutations":[408,471],"PIK3CA":[412,454,535],"marker":[415],"sensitivity.":[417],"subsequently":[419],"focused":[420],"on":[421,451,644],"colon":[422,446,458,478,541,555,591,613,650,747],"gave":[426],"strongest":[428],"drug":[430,602,639,675],"dependent":[431],"signature,":[432],"one":[434],"resistance.":[436],"A":[437],"panel":[438],"PI3K":[442],"pathway":[443],"differentiated":[445],"based":[450],"RAS":[452],"genotypes.":[455],"Ordering":[456],"revealed":[466],"striking":[468],"KRAS":[473,485,515,539,684,745],"within":[474],"already":[476],"resistant":[477,714],"set.":[480],"identified":[482,560,722],"specific":[486,492],"due":[489],"failure":[493,692,700],"inhibit":[495,695],"translational":[499],"repressor":[500],"4E-BP1":[501,696,728,779],"even":[502,538],"when":[503],"other":[504],"substrates":[506,761],"Resistance":[509],"correlated":[510,550,698],"amount":[513],"GTP-bound":[519],"form":[520],"canonical":[525],"mitogen":[526],"activated":[527],"signaling.":[530],"Finally,":[531],"introduction":[532],"mutant":[534,540,685,746],"sensitize":[537],"cells":[543],"4E-PB1":[552],"predictive":[561],"biomarker":[569,783],"reported":[571],"upon":[572],"functional":[573],"vivo.":[578],"Cell":[579],"documented":[583],"shortcomings,":[584],"worked":[587],"characterize":[589],"patient-derived":[593],"xenograft":[594],"(PDX)":[595],"model":[596,610],"early":[601],"discovery":[603],"validate":[605],"findings.":[607],"PDX":[609,652],"uses":[611],"metastatic":[612],"removed":[615],"patients":[617],"then":[620],"propagated":[621],"nude":[623],"mice.":[624],"Each":[625],"patient":[626],"tumor":[627],"expanded":[630],"cohort":[633],"identical":[635],"tumors,":[636],"trial":[640,670],"conducted":[643],"individual's":[646],"tumor.":[647],"model,":[653],"orally":[656],"bioavailable":[657],"acutely":[659],"continuous":[668],"dosing":[669],"however,":[671],"paralleled":[676],"observed":[679],"lines.":[682],"Single":[683],"refractory":[688],"treatment.":[690,704],"Overall,":[691],"durably":[694],"respond":[702],"discovered":[706,763],"set":[708],"inhibitor":[719],"defect":[724],"giving":[731],"rise":[732],"phenotype.":[735],"appears":[740],"patients.":[754],"differential":[756],"distinct":[759],"reveals":[764],"additional":[766],"layer":[767],"yet":[770],"uncharacterized":[771],"biological":[772],"control":[773],"pathway.":[778],"robust":[782],"drugs":[786],"should":[788],"strongly":[790],"considered":[791],"use":[794],"trials":[796],"agents.":[799]},"counts_by_year":[],"updated_date":"2026-09-26T08:19:03.415552","created_date":"2016-06-24T00:00:00"}
