Supplementary Material

Substance Mechanism Status in other cancers Status in GEP-NENs / Inhibitor of FDA approved for kidney FDA approved for Sunitinib malate several RTK cancer and for gastrointestinal progressive well- stromal tumors; differentiated pNENs in Multiple phase II, III and IV patients with unresectable, monotherapy trials and several locally advanced, or combination under assessment metastatic disease; Phase IV to observe efficacy and safety in pNENs (NCT01525550), (NCT00444795); Phase II in poorly- differentiated advanced NENs (NCT01215578); Phase II + Lantreotide in NENs (NCT01731925); Phase III in patients with islet cell carcinoma (NCT00428597) human mAb Phase III in pancreatic Phase II in metastatic well- (AMG 479) against IGF-1R adenocarcinoma differentiated carcinoid or (NCT01231347): has been pNET (NCT01024387) terminated; Treatment with single- Several monotherapy Phase I/II agent ganitumab failed to studies in solid cancer entities result in significant tumor (NCT01327612), responses [390] (NCT00563680), (NCT00719212); several combination under assessment NVP-AEW541 human mAb Preclinical [391-404] Preclinical [14, 135, 405] against IGF-1R human mAb Monotherapy Phase II in Phase I + Everolimus (IMC-A12) against IGF-1R recurrent solid cancer in advanced NE (NCT00831844), advanced carcinomas sarcoma (NCT00668148), (NCT01204476) Advanced liver cancer Phase II in metastatic (NCT00639509), NENs (NCT00781911) metastatic melanoma of the eye (NCT01413191), 2nd line therapy in metastatic prostate cancer and mesothelioma (NCT00520481), (NCT01160458); several combination under assessment MK-0646 human mAb Phase I in solid tumors Phase II in metastatic well- () against IGF-1R (NCT01431547), differentiated NENs (NCT00635778), (NCT00610129), (NCT00694356), CRC failed to result in (NCT00925015), significant tumor responses Breast cancer (NCT00759785) in monotherapy regimens and multiple myeloma [129] (NCT00701103); several combination under assessment inhibitor of IGF- Phase III in N/A (OSI-906) 1R and IR adrenocortical carcinoma (NCT00924989); Several phase I and II trials and several combination under assessment NVP-ADW742 IGF-1R Preclinical [406-409] N/A inhibitor BMS-536924 ATP- Preclinical [410-414] N/A (HY-10262, competitive CS-0117) IGF-1R and IR inhibitor BMS-754807 reversible Phase I monotherapy in Preclinical [21, 415, 416] inhibitor of IGF- neoplasms (NCT00898716) and 1R/IR family advanced solid cancer kinases, inhibits (NCT00569036); IGF-1R, IR, Phase I and II under assessment Met, TrkA and in several combinations TrkB EGFR inhibitor FDA approved for NSCLC and Preclinical [361, 417] (Iressa, several Phase IV in NSCLC; ZD-1839) Various phase II and III trials irreversibly Phase III monotherapy in head N/A (BIBW2992, inhibits and neck neoplasms Tovok) EGFR/HER2 (NCT01427478), (NCT01345669); in NSCLC (NCT01853826), (NCT00656136); Several phase I and II trials and several combination under assessment HER1/EGFR FDA approved for NSCLC, for Preclincial [241] HCl(OSI-744, inhibitor first-line treatment and CP358774, maintenance treatment of NSC718781) NSCLC; approved for pancreatic cancer; Several phase II and III trials and several combination under assessment EGFR and FDA approved for hormone- N/A (GW572016) ErbB2 inhibitor positive and HER2-positive advanced breast cancer and for HER2-overexpressing breast cancer; Several phase II and III trials and several combination under assessment AG-1478 EGFR inhibitor Preclinical [418-420] Preclinical [32] (Tyrphostin)

CI-1033 inhibitor of Phase II in lung and breast N/A (Canertinib, EGFR and neoplasms PD183805) ErbB2 (NCT00050830), (NCT00051051) CUDC-101 multi-target Phase I monotherapy in several N/A inhibitor cancer entities (NCT01702285), targeting (NCT01171924), HDAC, EGFR (NCT00728793) and HER2 Pelitinib EGFR inhibitor Phase II monotherapy N/A (EKB-569) in NSCLC (NCT00067548) and CRC (NCT00072748) epidermal Phase IV monotherapy in N/A (BPI-2009H) NSCLC (NCT01465243), receptor (EGFR) (NCT01720901), (NCT01646450); inhibitor Several phase II and III trials and several combination under assessment HER2 and Phase III monotherapy in breast N/A (HKI-272) EGFR inhibitor cancer (NCT00878709); Several phase I and II trials and several combination under assessment AZD4547 FGFR inhibitor Phase II in patients with Patients N/A targeting With FGFR1 or FGFR2 FGFR1, Amplified Tumors FGFR2, and (NCT01795768); FGFR3 Some phase I and combined studies EGFR mAb FDA approved for EGFR- Phase 2 in patients with expressing, metastatic colorectal metastatic carcinoid tumor cancer; and carcinoid syndrome Several phase II and III trials (NCT01172717) and several combination under assessment Suppl. 1: Selected inhibitors and antibodies targeting upstream receptors of the PI3K and MAPK pathway and that are currently under preclinical and clinical assessment in GEP-NENs and other cancer entities.

Substance Mechanism Status in other cancers Status in GEP-NENs Octreotide SSTR2 and 5 Phase II and III in FDA approved for metastatic (SMS 201-995) peptide hepatocellular carcinoma carcinoid tumors and VIPomas; agonist (NCT00495846), Multiple phase I-IV monotherapy (NCT00386984), studies in neuroendocrine tumore (NCT00241020); (NCT00171873), (NCT01578239); Phase II in liver cancer and assessment in several (NCT00257426); phase III combinations: e.g. + everolimus in breast cancer (NCT00412061), (NCT00113360), (NCT00002967); Phase II I (NCT01567488); + interferon alfa prostate cancer canceled (NCT00569127), (NCT00569127); due to lack of efficiency Phase II + (NCT00510224); Phase II (NCT00569127) & + fludarabine in non- (NCT01121939); Phase II + 5FU hodgkin’s lymphoma (NCT00953394); Phase II + (NCT00002779); phase IV in WDNEC (NCT01744249) in pituitary adenoma (NCT01371643); Phase II in thyroid cancer (NCT01270321) Lanreotide SSTR2 and 5 Phase II/III in Phase III in carcinoid syndrome (BIM23014) peptide hepatocellular carcinoma (NCT00774930), endocrine tumors agonist (NCT00495846) (NCT00353496); and in non- functioning entero-pancreatic endocrine tumor (NCT00842348), Phase IV in neuroendocrine tumors with carcinoid symptoms (NCT00681187), several phase II trials Pasireotide SSTR1, 2, 3 Phase II in thyroid cancer Phase II and III in patients with (SOM 230) and 5 peptide (NCT01270321); Phase II metastatic carcinoid disease agonist in hepatocellular carcinoma (NCT00690430), (NCT00088595); (NCT01639352), Phase I + everolimus in NENs (NCT01488487); Phase II + (NCT00804336), (NCT01263353); everolimus in uveal Phase II + everolimus in islet cell melanoma carcinoma (NCT01374451) (NCT01252251); Phase III in pancreatic cancer (NCT00994110); Phase II in prostate cancer (NCT01313559); Phase II in NE carcinoma of lung and thymus (NCT01563354); Phase II in non- functioning pituitary adenoma (NCT01283542), (NCT01620138); several phase I trials Vapreotide SSTR2 and 5 Phase III in pancreatic Phase III in in neuroendocrine (RC160) peptide cancer canceled due to lack gastro-intestinal tumors [421] agonist of response (NCT00014651) Seglitide SSTR2 and 5 N/A N/A (MK-678) peptide agonist L362,855 SSTR2, 3 N/A N/A and 5 peptide agonist BIM 23268 SSTR5 Preclinical [90, 120, 422- N/A peptide 424] agonist BIM 23197 SSTR2 and 5 Preclinical [120, 422, 423, N/A peptide 425] agonist BIM 23926 SSTR1 Preclinical [426-429] Preclinical [430] peptide agonist BIM 23120 SSTR2 Preclinical [425, 428-433] Preclinical [430] peptide agonist BIM 23206 SSTR5 Preclinical [425, 427-433] Preclinical [430] peptide agonist BIM 23745 SSTR1 Preclinical [426, 431, 432, N/A peptide 434] agonist NC8-12 SSTR2 and 3 Preclinical [435] N/A peptide agonist BIM-23A779 SSTR1, 2, 3 Preclinical [120, 424] N/A and 5 peptide agonist BIM23052 SSTR2, 3 Preclinical [436] N/A and 5 peptide agonist KE108 SSTR1-5 Preclinical [90, 437, 438] N/A peptide agonist L-054,264 SSTR2 non- N/A N/A peptide agonist L-054,522 SSTR2 non- Preclinical [54, 439, 440] N/A peptide agonist L-779,976 SSTR2 non- Preclinical [441] N/A peptide agonist L-817,818 SSTR5 non- Preclinical [90, 438, 441] N/A peptide agonist BIM-23A758 SSTR2/ Preclinical: [121] Preclinical: [122] D2R agonist BIM-23A760 SSTR2/ Preclincial: [120, 433, 442, Preclinical: [122] D2R 443] Phase II study in carcinoid syndrome agonist has been terminated due to poor inhibition of GH and IGF-1 (NCT01018953) BIM-23A387 SSTR2/ Preclinical: [121, 428, 444- N/A D2R 447] agonist BIM-23A761 SSTR2/ Preclincial: [121, 433, 448] N/A D2R agonist Suppl. 2 Selected non-radiolabeled SSTR agonstist under current clinical and preclinical assessment in GEP-NENs and other cancer entities.

Substance Mechanism Status in other cancers Status in GEP- NENs NVP-BEZ235 ATP- Monotherapy: Phase II in pNENs competitive Phase I/II (NCT01628913, inhibitor of class In PEComa and RCC NCT01658436) I PI3Ks and (NCT01690871) (NCT01453595); mTORC1 and Phase II/III C2 in transitional cell carcinoma (NCT01856101); And in several combinations LY294002 Inhibitor of Preclinical [449-457] Preclinical [131, p110α, p110δ 132] and p110β, and blocks autophagosome formation XL765/ dual inhibitor of Phase I in solid cancer N/A SAR254409 mTOR/PI3k for (NCT00485719) and recurrent mTOR, p110α, glioblastoma (NCT01240460); p110β, p110γ Combined therapy (NCT00704080), and p110δ (NCT00777699), (NCT01082068) Wortmannin PI3K, mTOR, Preclinical [458-463] N/A DNA-PK, MAPK GDC-0980/ inhibitor of Phase II in endometrial carcinoma N/A RG7422 PI3Kα, PI3Kβ, (NCT01455493), and RCC PI3Kδ and (NCT01442090); PI3Kγ and Phase I in Non- mTOR Hodgkin's lymphoma, solid cancers (NCT00854126); combined therapy PI-103 ATP- Preclinical [464-469] N/A competitive PI3K inhibitor of DNA-PK, p110α, mTORC1, PI3KC2β, p110δ, mTORC2, p110β, and p110γ GSK1059615 dual inhibitor of Phase I in solid tumors and lymphoma N/A PI3Kα, PI3Kβ, (NCT00695448), PI3Kδ, PI3Kγ Terminated due to lack of sufficient and mTOR, exposure DNA-PK PKI-587/ dual inhibitor of Phase I in neoplasms (NCT00940498) N/A PF-05212384 PI3Kα, PI3Kγ and Phase II in endometrial neoplasms and mTOR (NCT01420081) and combined therapy (NCT01347866) PF-04691502 ATP- Phase I Monotherapy (NCT00927823) N/A competitive, and II in combined approaches selective (NCT01658176), (NCT01430585) inhibitor of PI3K(α/β/δ/γ), mTOR, and Akt phosphorylation on T308/S473 (NVP)-BKM120 PI3K inhibitor Multiple Phase II monotherapy studies, N/A of p110α, e.g. in locally advanced cervical cancer p110β, p110δ (NCT01613677), endometrial cancer and p110γ (NCT01550380), thyroid cancer (NCT01830504), prostate cancer (NCT01385293), (NCT01695473), glioblastoma (NCT01339052), triple negative breast cancer (NCT01629615), CRC (NCT01591421); Several Phase I and multiple combined approaches SF1126 pan-PI3K Phase I in solid tumors N/A inhibitor (NCT00907205) PX-866 PI3K(α/δ/γ) Phase I in advanced solid tumors N/A (NCT00726583); Phase II in prostate cancer (NCT01331083) and glioblastoma (NCT01259869); Several combinations under phase I and II assessment XL-147/ reversible class I Phase II in endometrial cancer N/A SAR245408 PI3K inhibitor (NCT01013324), Phase I in for wild type glioblastoma (NCT01240460), solid and mutant tumors or lymphoma (NCT00486135); p110α Several combinations under phase I and II assessment ZSTK474 pan-class I PI3K Phase I/II in neoplasms N/A inhibitor (NCT01682473), (NCT01280487) GSK615 / dual inhibitor of Phase I in solid tumors or lymphomas N/A GSK1059615 PI3Kα, PI3Kβ, (NCT00695448) PI3Kδ, PI3Kγ and mTOR CH5132799 inhibitor of Phase I in solid tumors N/A PI3Kα (NCT01222546) GDC-0941 inhibitor of Phase I as 2nd line therapy in solid N/A PI3Kα, PI3Kβ, tumors (NCT00876109) and Non- PI3Kδ and Hodgkin's lymphoma PI3Kγ, Flt3 (NCT00876122); Several combinations under phase I and II assessment BAY80-6946 reversible PI3K Phase I in advanced cancer N/A inhibitor for (NCT00962611) and lymphoma PI3Kα and (NCT01660451); PI3Kβ Some combinations under phase I assessment CAL-101/ PI3K class I In Phase I,II and III assessment as N/A GS-1101 inhibitor of monotherapy and combined regimen in (Idelalisib) p110δ multiple hematologic neoplasms (NCT01306643), (NCT01539291), (NCT01644799), (NCT01569295), (NCT01796470), (NCT01539512) BYL719 Inhibitor of Phase I in Monotherapy of solid N/A PI3K (p110α) tumors (NCT01387321); Some combinations under phase I and II assessment MLN1117/ Inhibitor of Phase I in metastatic solid tumors N/A INK1117 PI3K (p110α) (NCT01449370) GSK2636771 Inhibitor of Phase I in PTEN-deficient solid tumors N/A PI3K (p110β) (NCT01458067) TGX-221 Inhibitor of Preclinical [470] N/A PI3K (p110β) Suppl. 3: PI3 kinase targeting biotherapy under current clinical and preclinical investigation

Substance Mechanism Status in other cancers Status in GEP- NENs Perifosine Targets the PH Phase III in multiple myeloma Preclinical (KRX-0401) domain of (NCT01002248), and [196] Akt1/2/3, + Capecitabine in CRC (NCT01097018); MEK 1/2, Several Phase I and II studies in solid and ERK1/2, JNK hematologic cancers; multiple combined approaches Triciribine Targets the PH Phase I in leukemia (NCT00642031), Preclinical and domain of metastatic cancer (NCT00363454); [169] VD-0002 Akt1/2/3, Phase I/II in combination with (Triciribine- DNA synthesis in breast cancer (NCT01697293) and ovarian phosphate, inhibitor cancer (NCT01690468) API-2, NSC- 280594) PHT-427 dual inhibitor Preclinical [471] N/A of Akt and PDK1 GDC-0068 Akt 1, 2, 3 Phase I in solid tumors (NCT01090960) and N/A in Phase I/II in combined approaches SR13668 Akt inhibitor Phase 0/I chemoprevention study in healthy N/A patients [472] (NCT00896207) GSK690693 Inhibitor of Phase I in solid cancer (NCT00493818) and N/A Akt 1, 2, 3 relapsed lymphoma (NCT00666081), both studies cancelled KP372-1 Inhibitor of Preclinical [473-475] N/A Akt, PDK-1, Flt3 A-443654 Inhibitor of Preclinical [476-479] N/A Akt XL-418 Inhibitor of Phase I in solid tumors (NCT00460278), N/A Akt / p70S6K suspended due to low drug exposure MK-2206 Allosteric Phase II monotherapy in ovarian cancer preclinical inhibitor of (NCT01283035), in esophageal and gastric [480], Akt 1, 2, 3 cancer (NCT01260701); Phase II in DLBCL (NCT01466868), (NCT01481129); metastatic NENs CRC (NCT01333475), (NCT01802320); (NCT01169649) AML (NCT01253447); endometrial cancer (NCT01307631), (NCT01312753); liver and biliary cancer (NCT01239355), (NCT01425879); head and neck cancer (NCT01349933), (NCT01370070); breast cancer (NCT01277757); kidney cancer (NCT01239342); various lymphomas (NCT01258998); Several combined approaches UCN-01 Inhibitor of Phase II monotherapy in T-cell lymphoma N/A PDK-1, Chk1, (NCT00082017), metastatic melanoma PKC isoforms (NCT00072189), several phase I and combination studies BX-320, Small Preclinical [481] N/A BX-795, molecule BX-912 PDK-1 inhibitors Suppl. 4: Akt and PDK-1 inhibitors under clinical and preclinical assessment in GEP-NENs and other cancer entities.

Substance Mechanism Status in other cancers Status in GEP-NENs Everolimus Allosteric FDA approved for subependymal Phase III—approved (RAD001) inhibitor of giant cell astrocytoma (SEGA); for pNENs mTORC1 for advanced hormone receptor- (NCT00510068) positive, HER2-negative breast [244]; cancer in combination with Under clinical phase I Exemestane, for advanced RCC after and II assessment in failure of treatment with Sunitinib or several combinations ; (NCT00942682, Several phase III and IV studies with NCT00576680, and without combinations ongoing NCT01263353, NCT01204476, NCT00843531, NCT01229943); Preclinical assessment in PDNEC [242] Temsirolimus Allosteric FDA approved for advanced RCC; Phase II in advanced (CCI-779) inhibitor of Several phase III and IV studies with NE carcinomas mTORC1 and without combinations ongoing (NCT00093782)[482] CC-223 ATP-competitive Phase I/II monotherapy for patients N/A inhibitor of with advanced solid tumors, Non- mTORC1/ Hodgkin lymphoma or multiple mTORC2 myeloma (NCT01177397) NVP-BEZ235 ATP-competitive Monotherapy: Phase II in pNENs inhibitor of class I Phase I/II (NCT01628913, PI3Ks and both In PEComa and RCC NCT01658436) mTORC1 and C2 (NCT01690871), (NCT01453595); and DNA-PK Phase II/III in transitional cell carcinoma (NCT01856101); And in several combinations LY2584702 Inhibitor of Phase I in solid tumors N/A p70S6K (NCT01241461) AZD-8055 Inhibitor of Phase I in solid tumors N/A mTORC1/ (NCT00731263), (NCT00973076); mTORC2 liver cancer (NCT00999882); and gliomas (NCT01316809) OSI-027 Inhibitor of Phase I in solid tumors and N/A mTORC1/ lymphoma (NCT00698243) mTORC2 INK-128/ Inhibitor of Phase I monotherapy in solid tumors N/A MLN0128 mTORC1/ (NCT01058707) and myelomas mTORC2 (NCT01118689) Suppl. 5: mTOR und p70S6K inhibitors under clinical and preclinical investigation in GEP-NENs and other cancer entities.

Substance Mechanism Status in other cancers Status in GEP- NENs inhibitor of FDA and EMA approved for N/A (PLX4032, mutant B- unresectable or metastatic melanoma RG7204, RafV600E with the BRAFV600E mutation RO5185426) (NCT01006980) (NCT01667419), Several Phase I, II and III, several combined approaches PLX-4720 inhibitor of Preclinical [325, 483-488] N/A mutant B-RafV600E and C-Raf- 1Y340D/ Y341D ATP- FDA approved for unresectable or N/A (GSK2118436) competitive metastatic melanoma with BRAF inhibitor of V600E mutation B-Raf, mutant (NCT01584648), B-RafV600E Several Phase I and II, and C-Raf Several combined approaches [489- 491] MLN2480 pan-Raf Phase I in N/A inhibitor solid tumors (NCT01425008) PF-04880594 inhibitor for Preclinical [492, 493] N/A B-Raf and C-Raf multi-target FDA approved for N/A (BAY73-4506, inhibitor for 2nd line therapy in Fluoro-Sorafenib) VEGFR1, Metastatic CRC VEGFR2, (NCT01103323) and VEGFR3, 2nd and 3rd line therapy of GIST PDGFRβ, Kit, (NCT01646593), Several Phase I and RET and C-Raf II, Several combined approaches AZ628 wild-type C-Raf Preclinical [494, 495] and mutant BRAFV600E

PD98059 non-ATP Preclinical Preclinical [132, competitive [496-501] 312] MEK inhibitor U-0126 inhibitor of Preclinical [502-515] Preclinical [274, (U0126-EtOH) MEK1 and 312, 385, 516, 517] MEK2 BAY43-9006 multikinase FDA Approved for advanced renal cell Phase II in (Sorafenib) inhibitor of C- carcinoma and hepatocellular Progressive Raf, B-Raf and carcinoma Metastatic VEGFR-2 Neuroendocrine Tumors (NCT00131911); and in NEN + Cyclo- phosphamide (NCT00605566); Preclinical [309] Raf265 B-Raf and Phase II in metastatic carcinoma Preclinical [135, VEGFR2 (NCT00304525), 310, 311] inhibitor Phase I + MEK162 in solid tumors with BRAFV600E Mutations (NCT01352273) Teriflunomide Tyrosine kinase Preclinical [518, 519] Preclinical [318] (TFN) inhibitor Leflunomide Tyrosine kinase Phase II Preclinical [318] (LFN) inhibitor, In brain and central Nervous System Tumors (NCT00003775), Phase II and III in combination in Stage IV Prostate Cancer (NCT00004071) Tautomycin serine/ Preclinical [520-522] Preclinical [319] (TTY) threonine phosphatase inhibitor ZM336372 C-Raf inhibitor Preclinical [523] Preclinical [321, 517] AZD6244 MEK1 inhibitor Phase II as monotherapy and in several N/A (, combined approaches in BRAF ARRY 142886) mutated solid tumors (NCT00888134),NSCLC (NCT01229150),(NCT01750281), (NCT00890825),(NCT00372788); in differentiated thyroid cancer (NCT01843062); Pancreatic cancer (NCT00372944),CRC (NCT01333475), (NCT00514761); Futher phase II studies in liver cancer, multiple myeloma, melanoma, breast cancer PD0325901 ATP- Phase I + PI3K pathway inhibitors in N/A competitive advanced cancer (NCT01347866); MEK inhibitor Both, Phase II in NSCLC (NCT00174369) and Phase I/II in breast cancer, colon cancer and melanoma (NCT00147550) have been prematurely terminated due to safety concerns GSK1120212 MEK1 and Phase III in N/A (, MEK2 inhibitor BRAF V600E/K Mutation-positive GSK212, Melanoma (NCT01245062), JTP-74057) (NCT01597908), (NCT01584648), (NCT01682083) CI-1040 ATP non- Phase II in N/A (PD184352) competitive NSCLC, Breast, Colon and Pancreatic MEK1/2 Cancer inhibitor (NCT00034827), (NCT00033384) BIX 02189 MEK5 inhibitor Preclinical [524] N/A AS703026 non-competitive Phase II in N-Ras mutated melanoma N/A (Pimasertib, inhibitor of (NCT01693068); MSC1936369B) MEK1/2 Phase I in solid tumors (NCT01668017), (NCT00982865), (NCT01390818); Hematological malignancies (NCT00957580); Some combined therapy studies TAK-733 non ATP- Phase I in advanced non- N/A competitive hematologic malignancies MEK inhibitor (NCT00948467) BIX 02188 MEK5 inhibitor Preclinical [524-526] N/A GDC-0973/ MEK inhibitor Phase 3 + vemurafenib in patients with N/A XL518 malignant melanoma (NCT01689519); Several phase I combinatory studies in solid cancers (NCT00467779), (NCT01562275), (NCT00996892), (NCT01506973) MEK162 MEK ihibitor Phase II in metastatic carcinoma N/A (NCT00304525), Phase I + Raf265 in solid tumors with BRAFV600E Mutations (NCT01352273) VEGFR/PDGR/ FDA approved for advanced soft tissue N/A Raf Inhibitor sarcoma and advanced renal cell carcinoma; Several phase III and IV studies BMS-908662/ RAF Inhibitor Phase I + Ipilimumab in patients with N/A XL281 melanoma (NCT01245556); Phase I/II in CRC (NCT01086267) Refametinib, MEK inhibitor, Phase I monotherapy in neoplasms (RDEA119, MAPK inhibitor (NCT01179295) and in patients with BAY 86-9766) advanced cancer [527] Phase I and II in several combinations Suppl. 6: Inhibitors and activators of Raf and MEK under preclinical and clinical assessment in GEP- NENs and other cancer entities.

Substance Mechanism Status in other cancers Status in GEP- NENs SCH772984 inhibitor of ERK1/2 Preclinical [528] N/A SB 203580 p38 MAPK inhibitor Preclinical [529, 530] Preclinical [132] and inhibitor of Akt phosphorylation BIRB 796 selective p38α MAPK Preclinical [531, 532] N/A (Doramapimod) inhibitor SB 202190 p38 MAPK inhibitor Preclinical [533, 534] N/A targeting p38α and p38β LY2228820 inhibitor of p38 Phase I in advanced cancer N/A MAPK (NCT01393990); Phase I/II in ovarian cancer (NCT01663857) VX-745 inhibitor of p38α Preclinical [535] N/A MAPK and p38β MAPK SP600125 inhibitor for JNK1, Preclinical [536-544] N/A (EI-305) JNK2 and JNK3 JNK-IN-8 irreversible JNK Preclinical [545] N/A inhibitor for JNK1, JNK2, JNK3 and JNK4 LY3007113 inhibitor of p38 Phase I in advanced cancer N/A MAPK (NCT01463631), BVD-523 ERK1/2 inhibitor Phase I/II in solid tumors N/A (NCT01781429) SCH772984 inhibitor of ERK1/2 Preclinical [528] N/A SB 203580 p38 MAPK inhibitor Preclinical [529, 530] Preclinical [132] and inhibitor of Akt phosphorylation BIRB 796 selective p38α MAPK Preclinical [531, 532] N/A (Doramapimod) inhibitor SB 202190 p38 MAPK inhibitor Preclinical [533, 534] N/A targeting p38α and p38β LY2228820 inhibitor of p38 Phase I in advanced cancer N/A MAPK (NCT01393990); Phase I/II in ovarian cancer (NCT01663857) VX-745 inhibitor of p38α Preclinical [535] N/A MAPK and p38β MAPK SP600125 inhibitor for JNK1, Preclinical [536-544] N/A (EI-305) JNK2 and JNK3 JNK-IN-8 irreversible JNK Preclinical [545] N/A inhibitor for JNK1, JNK2, JNK3 and JNK4 LY3007113 inhibitor of p38 Phase I in advanced cancer N/A MAPK (NCT01463631), BVD-523 ERK1/2 inhibitor Phase I/II in solid tumors N/A (NCT01781429) Suppl. 7: Selected MAPK inhibitors under clinical and preclinical investigation in GEP-NENs and other cancer entities.