Linking somatic genetic alterations in cancer to therapeutics

Current Opinion in Cell Biology

Volumn 21, Issue 2, 2009, Pages 304-310

  Stuart, Darrin ^a   Sellers, William R ^a  

^a NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BCR ABL PROTEIN; CETUXIMAB; DASATINIB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERLOTINIB; GEFITINIB; IMATINIB; LAPATINIB; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; NILOTINIB; PANITUMUMAB; PROTEIN RET; RAF PROTEIN; RETINOIC ACID; STEM CELL FACTOR; SUNITINIB; TRASTUZUMAB;

BREAST CANCER; CHRONIC MYELOID LEUKEMIA; COLON CANCER; DERMATOFIBROSARCOMA PROTUBERANS; DRUG TARGETING; ENDOMETRIUM CANCER; GASTROINTESTINAL STROMAL TUMOR; HUMAN; HYPEREOSINOPHILIC SYNDROME; KIDNEY CARCINOMA; LUNG ADENOCARCINOMA; LUNG CANCER; LUNG NON SMALL CELL CANCER; MELANOMA; MYELOPROLIFERATIVE DISORDER; PRIORITY JOURNAL; PROMYELOCYTIC LEUKEMIA; PROTEIN EXPRESSION; REVIEW; SOMATIC MUTATION; STOMACH CANCER; THYROID CARCINOMA; TREATMENT RESPONSE;

CLINICAL TRIALS AS TOPIC; DNA MUTATIONAL ANALYSIS; GENE TARGETING; HUMANS; MUTATION; NEOPLASMS; PROTO-ONCOGENE PROTEINS C-KIT; RECEPTOR, EPIDERMAL GROWTH FACTOR;

EID: 63749109364     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ceb.2009.02.001     Document Type: Review

References (64)

1. Cahill D.P., Kinzler K.W., Vogelstein B., and Lengauer C. Genetic instability and Darwinian selection in tumours. Trends Cell Biol 9 (1999) M57-M60
2. Jones S., Chen W.-d., Parmigiani G., Diehl F., Beerenwinkel N., Antal T., Traulsen A., Nowak M.A., Siegel C., Velculescu V.E., et al. Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci U S A 105 (2008) 4283-4288
3. Druker B.J. Translation of the Philadelphia chromosome into therapy for CML. Blood 112 (2008) 4808-4817
4. Thomas R.K., Baker A.C., DeBiasi R.M., Winckler W., LaFramboise T., Lin W.M., Wang M., Feng W., Zander T., MacConnaill L.E., et al. High-throughput oncogene mutation profiling in human cancer. Nat Genet 39 (2007) 347-351. Established assays to genotype 238 known mutations in 17 oncogenes and screened 1000 tumor specimens, demonstrating the feasibility of scaling the approach to clinical application. Identified previously unrecognized mutations in several tumor types and a relatively high number of co-occurring mutations.
5. Huang M.E., Ye Y.C., Chen S.R., Chai J.R., Lu J.X., Zhoa L., Gu L.J., and Wang Z.Y. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72 (1988) 567-572
6. de Thé H., Lavau C., Marchio A., Chomienne C., Degos L., and Dejean A. The PML-RAR[alpha] fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66 (1991) 675-684
7. Kakizuka A., Miller W.H., Umesono K., Warrell R.P., Frankel S.R., Murty V.V.V.S., Dmitrovsky E., and Evans R.M. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR[alpha] with a novel putative transcription factor, PML. Cell 66 (1991) 663-674
8. Slamon D.J., Clark G.M., Wong S.G., Levin W.J., Ullrich A., and McGuire W.L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235 (1987) 177-182
9. Pegram M.D., Lipton A., Hayes D.F., Weber B.L., Baselga J.M., Tripathy D., Baly D., Baughman S.A., Twaddell T., Glaspy J.A., et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16 (1998) 2659-2671
10. Seidman A.D., Fornier M.N., Esteva F.J., Tan L., Kaptain S., Bach A., Panageas K.S., Arroyo C., Valero V., Currie V., et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 19 (2001) 2587-2595
11. Geyer C.E., Forster J., Lindquist D., Chan S., Romieu C.G., Pienkowski T., Jagiello-Gruszfeld A., Crown J., Chan A., Kaufman B., et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355 (2006) 2733-2743
12. Heinrich M.C., Corless C.L., Demetri G.D., Blanke C.D., von Mehren M., Joensuu H., McGreevey L.S., Chen C.-J., Van den Abbeele A.D., Druker B.J., et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21 (2003) 4342-4349
13. Hirota S., Isozaki K., Moriyama Y., Hashimoto K., Nishida T., Ishiguro S., Kawano K., Hanada M., Kurata A., Takeda M., et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279 (1998) 577-580
14. Lynch T.J., Bell D.W., Sordella R., Gurubhagavatula S., Okimoto R.A., Brannigan B.W., Harris P.L., Haserlat S.M., Supko J.G., Haluska F.G., et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (2004) 2129-2139. Identified activating EGFR mutations or small in-frame deletions in eight of nine NSCLC patients responding to gefitinib, while zero of seven nonresponders had these mutations. First molecular correlate for response for EGFR inhibitor.
15. Paez J.G., Janne P.A., Lee J.C., Tracy S., Greulich H., Gabriel S., Herman P., Kaye F.J., Lindeman N., Boggon T.J., et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304 (2004) 1497-1500. Identified activating EGFR mutations or small in-frame deletions in NSCLC tumors that responded to gefitinib. Demonstrated that EGFR mutations are more prevalent in Japanese NSCLC patients than in patients from the U.S., providing an explanation for the higher response rates observed in this population.
16. Takano T, Fukui T, Ohe Y, Tsuta K, Yamamoto S, Nokihara H, Yamamoto N, Sekine I, Kunitoh H, Furuta K, et al.: EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J Clin Oncol 2008:JCO.2008.2016.7254. First demonstration of a statistically significant survival benefit for patients with EGFR mutation treated with gefitinib. Also demonstrated that EGFR mutation may be a positive prognostic factor for survival, independent of treatment with gefitinib.
17. Sartore-Bianchi A., Moroni M., Veronese S., Carnaghi C., Bajetta E., Luppi G., Sobrero A., Barone C., Cascinu S., Colucci G., et al. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol 25 (2007) 3238-3245. A large retrospective analysis demonstrating a correlation between EGFR gene copy number and progression free survival in patients treated with panitumumab. Study included a best supportive care arm allowing the investigators to demonstrate that EGFR gene copy number is not a positive prognostic factor.
18. Heinrich M.C., Corless C.L., Duensing A., McGreevey L., Chen C.-J., Joseph N., Singer S., Griffith D.J., Haley A., Town A., et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299 (2003) 708-710
19. Simon M.-P., Pedeutour F., Sirvent N., Grosgeorge J., Minoletti F., Coindre J.-M., Terrier-Lacombe M.-J., Mandahl N., Craver R., Blin N., et al. Deregulation of the platelet-derived growth factor [beta]-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma. Nat Genet 15 (1997) 95-98
20. Rubin B.P., Schuetze S.M., Eary J.F., Norwood T.H., Mirza S., Conrad E.U., and Bruckner J.D. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J Clin Oncol 20 (2002) 3586-3591
21. Cools J., DeAngelo D.J., Gotlib J., Stover E.H., Legare R.D., Cortes J., Kutok J., Clark J., Galinsky I., Griffin J.D., et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348 (2003) 1201-1214
22. Pardanani A., and Tefferi A. Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood 104 (2004) 1931-1939
23. Inui T., Asakawa A., Morita Y., Mizuno S., Natori T., Kawaguchi A., Murakami M., Hishikawa Y., and Inui A. HER-2 overexpression and targeted treatment by trastuzumab in a very old patient with gastric cancer. J Intern Med 260 (2006) 484-487
24. Jewell E., Secord A.A., Brotherton T., and Berchuck A. Use of trastuzumab in the treatment of metastatic endometrial cancer. Int J Gynecol Cancer 16 (2006) 1370-1373
25. Rebischung C., Barnoud R., Stefani L., Faucheron J.-L., and Mousseau M. The effectiveness of trastuzumab (Herceptin) combined with chemotherapy for gastric carcinoma with overexpression of the c-erbB2 protein. Gastric Cancer 8 (2005) 249-252
26. Stephens P., Hunter C., Bignell G., Edkins S., Davies H., Teague J., Stevens C., O'Meara S., Smith R., Parker A., et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431 (2004) 525-526
27. Cappuzzo F., Bemis L., and Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med 354 (2006) 2619-2621
28. Davies H., Bignell G.R., Cox C., Stephens P., Edkins S., Clegg S., Teague J., Woffendin H., Garnett M.J., Bottomley W., et al. Mutations of the BRAF gene in human cancer. Nature 417 (2002) 949-954
29. Solit D.B., Garraway L.A., Pratilas C.A., Sawai A., Getz G., Basso A., Ye Q., Lobo J.M., She Y., Osman I., et al. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439 (2005) 358-362. Using integrated genetic and pharmacologic approaches, this study demonstrated the exquisite sensitivity of BRAF mutant tumor cells to MEK inhibitors compared to RAS mutant tumor cells or cells wild-type for RAS and BRAF. This study demonstrated that BRAF mutant tumors should be targeted in clinical trials with MEK inhibitors.
30. Tsai J., Lee J.T., Wang W., Zhang J., Cho H., Mamo S., Bremer R., Gillette S., Kong J., Haass N.K., et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 105 (2008) 3041-3046
31. Dummer R., Robert C., Chapman P.B., Sosman J.A., Middleton M., Bastholt L., Kemsley K., Cantarini M.V., Morris C., and Kirkwood J.M. AZD6244 (ARRY-142886) vs Temozolomide (TMZ) in Patients (pts) with Advanced Melanoma: An Open-label, Randomized, Multicenter, Phase II Study (2008), American Society of Clinical Oncology, Chicago
32. Olivero M., Valente G., Bardelli A., Longati P., Ferrero N., Cracco C., Terrone C., Rocca-Rossettie S., Comoglio P., and Di Renzo M. Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family. Int J Cancer 82 (1999) 640-643
33. Lanzi C., Cassinelli G., Nicolini V., and Zunino F. Targeting RET for thyroid cancer therapy. Biochem Pharmacol 77 (2009) 297-309
34. Kris M.G., Natale R.B., Herbst R.S., Lynch Jr. T.J., Prager D., Belani C.P., Schiller J.H., Kelly K., Spiridonidis H., Sandler A., et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290 (2003) 2149-2158
35. Pao W., Miller V., Zakowski M., Doherty J., Politi K., Sarkaria I., Singh B., Heelan R., Rusch V., Fulton L., et al. EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (2004) 13306-13311
36. Inoue A., Suzuki T., Fukuhara T., Maemondo M., Kimura Y., Morikawa N., Watanabe H., Saijo Y., and Nukiwa T. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 24 (2006) 3340-3346
37. Sequist L.V., Martins R.G., Spigel D., Grunberg S.M., Spira A., Janne P.A., Joshi V.A., McCollum D., Evans T.L., Muzikansky A., et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 26 (2008) 2442-2449
38. Kobayashi S., Boggon T.J., Dayaram T., Janne P.A., Kocher O., Meyerson M., Johnson B.E., Eck M.J., Tenen D.G., and Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352 (2005) 786-792
39. Pao W., Miller V.A., Politi K.A., Riely G.J., Somwar R., Zakowski M.F., Kris M.G., and Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2 (2005) e73
40. Kosaka T., Yatabe Y., Endoh H., Yoshida K., Hida T., Tsuboi M., Tada H., Kuwano H., and Mitsudomi T. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 12 (2006) 5764-5769
41. Yun C.-H., Mengwasser K.E., Toms A.V., Woo M.S., Greulich H., Wong K.-K., Meyerson M., and Eck M.J. The T790 M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 105 (2008) 2070-2075
42. Bean J., Brennan C., Shih J.-Y., Riely G., Viale A., Wang L., Chitale D., Motoi N., Szoke J., Broderick S., et al. MET amplification occurs with or without T790 M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104 (2007) 20932-20937
43. Engelman J.A., Zejnullahu K., Mitsudomi T., Song Y., Hyland C., Park J.O., Lindeman N., Gale C.-M., Zhao X., Christensen J., et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316 (2007) 1039-1043
44. Tang Z., Du R., Jiang S., Wu C., Barkauskas D.S., Richey J., Molter J., Lam M., Flask C., Gerson S., et al. Dual MET-EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer. Br J Cancer 99 (2008) 911-922
45. Cappuzzo F., Finocchiaro G., Rossi E., Janne P.A., Carnaghi C., Calandri C., Bencardino K., Ligorio C., Ciardiello F., Pressiani T., et al. EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 19 (2008) 717-723
46. Moroni M., Veronese S., Benvenuti S., Marrapese G., Sartore-Bianchi A., Di Nicolantonio F., Gambacorta M., Siena S., and Bardelli A. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 6 (2005) 279-286
47. Personeni N., Fieuws S., Piessevaux H., De Hertogh G., De Schutter J., Biesmans B., De Roock W., Capoen A., Debiec-Rychter M., Van Laethem J.-L., et al. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res 14 (2008) 5869-5876
48. Benvenuti S., Sartore-Bianchi A., Di Nicolantonio F., Zanon C., Moroni M., Veronese S., Siena S., and Bardelli A. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67 (2007) 2643-2648. This study demonstrated that colorectal tumors with K-Ras or B-Raf mutations are less likely to respond to cetuximab or panitumumab. Confirmed preclinically that a cell line with increased EGFR gene copy number becomes resistant to cetuximab following transfection with mutant K-Ras.
49. Cappuzzo F., Varella-Garcia M., Finocchiaro G., Skokan M., Gajapathy S., Carnaghi C., Rimassa L., Rossi E., Ligorio C., Di Tommaso L., et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer 99 (2008) 83-89
50. Amado R.G., Wolf M., Peeters M., Van Cutsem E., Siena S., Freeman D.J., Juan T., Sikorski R., Suggs S., Radinsky R., et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26 (2008) 1626-1634
51. Freeman D.J., Juan T., Reiner M., Hecht R., Meropol N.J., Berlin J., Mitchell E., Sarosi I., Radinsky R., and Amado R.G. Association of K-ras mutational status and clinical outcomes in patients with metastatic colorectal cancer receiving panitumumab alone. Clin Colorectal Cancer 7 (2008) 184-190
52. Gorre M.E., Mohammed M., Ellwood K., Hsu N., Paquette R., Rao P.N., and Sawyers C.L. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293 (2001) 876-880
53. Tamborini E., Bonadiman L., Greco A., Albertini V., Negri T., Gronchi A., Bertulli R., Colecchia M., Casali P.G., Pierotti M.A., et al. A new mutation in the KIT ATP pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient. Gastroenterology 127 (2004) 294-299
54. Chen L.L., Trent J.C., Wu E.F., Fuller G.N., Ramdas L., Zhang W., Raymond A.K., Prieto V.G., Oyedeji C.O., Hunt K.K., et al. A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 64 (2004) 5913-5919
55. Nagata Y., Lan K.-H., Zhou X., Tan M., Esteva F.J., Sahin A.A., Klos K.S., Li P., Monia B.P., Nguyen N.T., et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6 (2004) 117-127
56. Berns K., Horlings H.M., Hennessy B.T., Madiredjo M., Hijmans E.M., Beelen K., Linn S.C., Gonzalez-Angulo A.M., Stemke-Hale K., Hauptmann M., et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12 (2007) 395-402. Using an unbiased genome-wide RNAi screen, identified PTEN as a modulator of trastuzumab resistance and then confirmed that PI3K mutations also result in resistance. Patients with low PTEN expression or PI3K mutations are more likely to have disease progression on trastuzumab therapy.
57. Heinrich MC, Owzar K, Corless CL, Hollis D, Borden EC, Fletcher CDM, Ryan CW, von Mehren M, Blanke CD, Rankin C, et al.: Correlation of kinase genotype and clinical outcome in the North American intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by cancer and leukemia group B and Southwest Oncology Group. J Clin Oncol 2008:JCO.2008.2017.4284.
58. Wyman K., Atkins M.B., Prieto V., Eton O., McDermott D.F., Hubbard F., Byrnes C., Sanders K., and Sosman J.A. Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma. Cancer 106 (2006) 2005-2011
59. Ugurel S., Hildenbrand R., Zimpfer A., La Rosee P., Paschka P., Sucker A., Keikavoussi P., Becker J.C., Rittgen W., Hochhaus A., et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92 (2005) 1398-1405
60. Curtin J.A., Busam K., Pinkel D., and Bastian B.C. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24 (2006) 4340-4346. The observation that BRAF and NRAS mutations are less frequent in certain melanoma subtypes lead to the investigation of other possible genetic alterations that could activate the Ras/Raf pathway. Identified activating KIT mutations in these tumors with a frequency of 28-39% in melanoma tumors from acral, mucosal, and chronically sun-damaged skin.
61. Hodi F.S., Friedlander P., Corless C.L., Heinrich M.C., Mac Rae S., Kruse A., Jagannathan J., Van den Abbeele A.D., Velazquez E.F., Demetri G.D., et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (2008) 2046-2051. Based on the discovery by Curtin et al. that activating mutations in KIT occur in specific subtypes of melanoma, identified a patient with anal mucosal melanoma that expressed mutant KIT. Treatment with imatinib resulted in a major response and significant improvement in symptoms.
62. Kim K.B., Eton O., Davis D.W., Frazier M.L., McConkey D.J., Diwan A.H., Papadopoulos N.E., Bedikian A.Y., Camacho L.H., Ross M.I., et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer 99 (2008) 734-740
63. Maheswaran S., Sequist L.V., Nagrath S., Ulkus L., Brannigan B., Collura C.V., Inserra E., Diederichs S., Iafrate A.J., Bell D.W., et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359 (2008) 366-377. This study demonstrated that circulating tumor cells from NSCLC patients could be isolated in the peripheral blood, genotyped for EGFR mutations and in 11/12 cases mutations in a primary biopsy-matched mutation in the circulating tumor cells.
64. Engelman J.A., Chen L., Tan X., Crosby K., Guimaraes A.R., Upadhyay R., Maira M., McNamara K., Perera S.A., Song Y., et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14 (2008) 1351-1356. This study describes the activity of a PI3K inhibitor in genetically engineered mouse lung tumor models expressing mutant KRAS or mutant PIK3CA. KRAS mutant lung tumors are insensitive to PI3K inhibitor but highly sensitive to combination of MEK inhibitor + PI3K inhibitor.