Personalized medicine for effective treatment of non-small-cell lung cancer with targeted therapies

Duong Hong Quan


Lung cancer is the most common cause of cancer death worldwide, with most deaths having distant metastases. It has become increasingly complex to get effective treatment for lung cancer patients. While generalized medicine with traditional therapy resulted in comparatively poor response, personalized medicine has been well known to be an important strategy for effective treatment of lung cancer, with current focus on significant detection of clinical oncogenic drivers responsible for tumor initiation and maintenance and development of drug resistance. In lung cancer, especially in non-small-cell lung cancer (NSCLC), EGFR, ALK, RET, ROS1, BRAF, KRAS, NRAS, PIK3CA, DDR2, MET, ERBB2 have been reported to be key oncogenic drivers, which are targeted in the development and application of targeted therapeutic drugs. Personalized medicine based on these oncogenic drivers is highly recommended for treatment of advanced NSCLC patients. In this article, the significant application of personalized medicine based on the key oncogenic drivers for effective treatment of NSCLC with targeted therapeutic drugs is reviewed.



Personalized medicine, targeted therapy, non-small-cell lung cancer, treatment.

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Aviel-Ronen S., Blackhall F. H., Shepherd F. A., Tsao M. S., 2006. K-ras mutations in non-small-cell lung carcinoma: a review. Clin. Lung. Cancer., 8(1): 30−38.

Bergethon K., Shaw A. T., Ou S. H., Katayama R., Lovely C. M., McDonald N. T., Massion P. P., Siwak-Tapp C., Gonzalez A., Fang R., Mark E. J., Batten J. M., Chen H., Wilner K. D., Kwak E. L., Clark J. W., Carbone D. P., Ji H., Engelman J. A., Mino-Kenudson M., Pao W., Lafrate A. J., 2012. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin Oncol., 30(8): 863−870.

Bray F., Ferlay J., Soerjomataram I., Siegel R. L., Torre L. A., Jemal A., 2018. Global caner statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer. J. Clin., 68(6): 394−424.

Camidge D. R., Kono S. A., Flacco A., Tan A.C., Doebele R.C., Zhou Q., Crino L., Franklin W.A., Varella-Garcia M., 2010. Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. Clin. Cancer. Res., 16(22): 5581−5590.

Cardarella S., Ogino A., Nishino M., Butaney M., Shen J., Lydon C., Yeap B. Y., Sholl L. M., Johnson B.E., Jänne P. A., 2013. Clinical, pathologic and biologic features associated with BRAF mutations in non-small cell lung cancer. Clin. Cancer. Res., 19(16): 4532−4540.

Chong C. R and Jänne P. A., 2013. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med., 19(11): 1389−1400.

Du X., Shao Y., Qin H. F., Tai Y. H., Gao H. J., 2018. ALK-rearrangment in non-small-cell lung cancer (NSCLC). Thorar. Cancer., 9(4): 423−430.

Gainor J. F and Shaw A. T., 2013. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist., 18(7): 865−975.

Gainor J. F., Varghese A. M., Ou S. H., Kabraji S., Awad M. M., Katayama R., Pawlak A., Mino-Kenudson M., Yeap B. Y., Riely G. J., Iafrate A. J., Arcila M. E., Ladanyi M, Engelman J. A., Dias-Santagata D and Shaw A. T., 2013. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. Clin. Cancer. Res., 19(15): 4273−4281.

Gautschi O., Milia J., Filleron T., Wolf J., Carbone D. P., Owen D., Camidge R., Narayanan V., Doebele R. C., Besse B., Remon-Masip J., Janne P. A., Awad M. M., Peled N., Byoung C. C., Karp D. D., Van Den Heuvel M., Wakelee H.A., Neal J. W., Mok T. S. K., Yang J. C. H., Ou S. I., Pall G., Froesch P., Zalcman G., Gandara D. G., Riess J. W., Velcheti V., Zeidler K., Diebold J., Früh M., Michels S., Monnet I., Popat S., Rosell R., Karachaliou N., Rothschild S. I, Shih J. Y., 2017. Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry. J. Clin. Oncol., 35(13): 1403−1410.

Gridelli C., Rossi A., Carbone D. P., Guarize J., Karachaliou N., Mok T., Petrella F, Spaggiari L., Rosell R., 2015. Non-small-cell lung cancer. Nat. Rev. Dis. Primers.,1: 15009.

Guo Y., Cao R., Zhang X., Huang L., Sun L., Zhao J., Ma J., Han C., 2019. Recent progress in rare oncogenic drivers and targeted therapy for non-small cell lung cancer. Onco. Targets. Ther., 12: 10343−10360.

Horn L and Pao W., 2009. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J. Clin. Oncol., 27(26): 4232−4235.

Inamura K., Takeuchi K., Togashi Y., Nomura K., Ninomiya H., Okui M., Satoh Y., Okumura S., Nakagama K., Soda M., Choi Y. L., Niki T., Mano H., Ishikawa Y., 2008. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J. Thorac. Oncol., 3(1): 13−17.

Katayama, 2017. Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)-rearranged lung cancer. Pharmacol. Ther., 177: 1−8.

Kohno T., Ichikawa H., Totoki Y., Yasuda K., Hiramoto M., Nammo T., Sakamoto H., Tsuta K., Furuta K., Shimada Y., Iwakawa R., Ogiwara H., Oike T., Enari M., Schetter A. J., Okayama H., Haugen A., Skaug V., Chiku S., Yamanaka I., Arai Y., Watanabe S., Sekine I., Ogawa S., Harris C. C., Tsuda H., Yoshida T., Yokota J., Shibata T., 2012. KIF5B-RET fusions in lung adenocarcinoma. Nat. Med., 18(3): 375−377.

Labrador J. P., Azcoitia V., Tuckermann J., Lin C., Olaso E., Manes S., Brückner K., Goergen J. L., Lemke G., Yancopoulos G., Angel P., Martinez C., Klein R., 2001. The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO. Rep., 2(5): 446−452.

Li B. T., Ross D. S., Aisner D. L., Chaft J. E., Hsu M., Kako S. L., Kris M. G., Varella-Garcia M., Arcila M. E., 2016. HER2 amplication and HER2 mutation are distinct molecular targets in lung cancers. J. Thorac. Oncol., 11(3): 414−419.

Li D., Ambrogio L., Shimamura T., Kubo S., Takahashi M., Chirieac L. R., Padera R. F., Shapiro G. I., Baum A., Himmelsbach F., Rettig W. J., Meyerson M., Solca F., Breulich H., Wong K. K., 2008. BIBW2992, an irreversibla EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene., 27(34): 4702−4711.

Li T., Kung H. J., Mack P. C., Gandara D. R., 2013. Genotyping and genomic profiling of non-small-cell lung cancer: Implications for current and future therapies. J. Clin. Oncol., 31(8): 1039−1049.

Lin J. J. and Shaw A. T., 2017. Recent advances in targeting ROS1 in lung cancer. J. Thorac Oncol., 12(11): 1611−1625.

Lin J. J., Kennedy E., Sequist L. V., Brastianos P. K., Goodwin K. E., Stevens S., Wanat A. C., Stober L. L., Digumarthy S. R., Engelman J. A., Shaw A. T., Gainor J. F., 2016. Clinical activity of Alectinib in advanced RET-rearranged non-small cell lung cancer. J. Thorac. Oncol., 11(11): 2027−2032.

Lin J. J., Riely G. J., Shaw A. T., 2017. Targeting ALK: precision medicine takes on drug resistance. Cancer. Discov., 7(2): 137−155.

Marchetti A., Felicioni L., Malatesta S., Grazia Sciarrotta M., Guetti L., Chella A., Viola P., Pullara C., Mucilli F., Buttitta F., 2011. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J. Clin. Oncol., 29(26): 3574−3579.

Mazières J., Zalcman G., Crinò L., Biondani P., Barlesi F., Filleron T., Dingemans A. M., Léna H., Monnet I., Rothschild S. I., Cappuzzo F., Besse B., Thiberville L., Rouvière D., Dziadziuszko R., Smit E. F., Wolf J., Spirig C., Pecuchet N., Leenders F., Heuckman J. M., Diebold J., Milia J. D., Thomas R. K., Gautschi O., 2015. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J. Clin. Oncol., 33(9): 992−999.

Mok T. S., Wu Y. L., Ahn M. J., Garassino M. C., Kim H. R., Ramalingam S. S., Shepherd F. A., He Y., Akamatsu H., Theelen W. S., Lee C. K., Sebastian M., Templeton A., Mann H., Marotti M., Ghiorghiu S., Papadimitrakopoulou V. A., AURA3 investigators, 2017. Osimertinib or platinum-pemetrexed in EGFR T790M positive lung cancer. N. Engl. J. Med., 376(7): 629−640.

O’Leary C. G., Andelkovic V., Ladwa R., Pavlakis N., Zhou C., Hirsch F., Richard D., ÓByrne K., 2019. Targeting BRAF mutations in no-small cell lung cancer. Transl. Lung. Cancer. Res., 8(6): 1119−1124.

Ohashi K., Sequist L. V., Arcila M. E., Lovly C. M., Chen X., Rudin C. M., Moran T., Camidge D. R, Vnencak-Jones C.L., Berry L., Pan Y., Sakaki H., Engelman J. A., Garon E. B., Dubinett S. M., Franklin W. A., Riely G. J., Sos M. L., Kris M. G., Dias-Santagata D., Ladanyi M., Bunn P. A Jr., Pao W., 2013. Characteristics of lung cancers harboring NRAS mutations. Clin. Cancer. Res.. 19(9): 2584−2591.

Pfister D. G., Johson D. H., Azzoli C. G., Sause W., Smith T. J., Baker S., Olak J., Stover D., Strawn J. R., Turrisi A. T., Somerfield M. R., 2004. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: Updated 2003. J. Clin. Oncol., 22: 330−353.

Reungwetwattana T and Dy G. K., 2013. Targeted therapies in development for non-small cell lung cancer. J. Carcinog., 12: 22.

Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J. M., Yuan J., Bakalarski C.E., Villen J., Kornhauser J. M., Smith B., Li D., Zhou X., Gygi S. P., Gu T. L., Polakiewicz R. D., Rush J., Comb M. J., 2007. Global survey of phosphatyrosine signaling identifies oncogenic kinases in lung cancer. Cell., 131(6): 1190−1203.

Rosas G., Ruiz R., Araujo J. M., Pinto J. A., Mas L., 2019. ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer. Crit. Rev. Oncol. Hematol., 136: 48−55.

Sarfaty M., Moore A., Neiman V., Dudnik E., IIouze M., Gottfriend M., Katznelson R., Nechushtan H., Sorotsky H. G., Paz K., Katz A., Saute M., Wolner M., Moskovitz M., Miller V., Elvin J., Lipson D., Ali S., Gutman L. S., Dvir A., Gordon N., Peled N., 2017. RET fusion lung carcinoma: Response to therapy and clinical features in a case series of 14 patients. Clin. Lung. Cancer., 18(4): e223−e232.

Sharma S. V., Bell D. W., Settleman J., Haber D. A., 2007. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer., 7(3): 169−181.

Shaw A. T., Gandhi L., Gadgeel S., Riely G. J., Cetnar J., West H., Camidge D. R., Socinski M. A., Chiappori A., Mekhail T., Chao B. H., Borghaei H., Gold K. A., Zeater A., Bordogna W., Balas B., Puig O., Henschel V., Ou S. I., Study investigators, 2016. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet. Oncol., 17(2): 234−242.

Shaw A. T, Kim D. W, Mehra R, Tan D. S., Felip E., Chow L. Q., Camidge D. R., Vansteenkiste J., Sharma S., De Pas T., Riely G. J., Solomon B. J., Wolf J., Thomas M., Schuler M., Liu U., Santoro A, Lau Y. Y., Goldwasser M., Boral A. L., Engelman J. A., 2014. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med., 370(13): 1189−1197.

Shaw A. T., Kim D. W., Nakagawa K., Seto T., Crino L., Ahn M.J., De Pá T., Bese B., Solomon B.J., Blackhall F., Wu Y. L., Thomas M., ÓByrne K.J., Moro-Sibulot D., Camidge D. R., Mok T., Hirsh V., Riely G. J., Lyer S., Tassell V., Polli A., Wilner K. D., Jänne P. A., 2013. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N. Engl. J. Med., 368(25): 2385−2394.

Shaw A. T., Ou S. H., Bang Y. J., Camidge D. R., Solomon B. J., Salgia R., Riely G. J., Varella-Garcia M., Shapiro G. I., Costa D. B., Doebele R. C., Le L. P., Zheng Z., Tan W., Stephenson P., Shreeve S. M., Tye L. M., Christensen J. G., Wilner K. D., Clark J. W., Lafrate A. J., 2014. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med., 371(21): 1963−1971.

Shaw A. T., Yeap B. Y., Mino-Kenudson M., Digumarthy S. R., Costa D. B., Heist R. S., Solomon B., Stubbs H., Admane S., MeDermott U., Settleman J., Kobayashi S., Mark E. J., Rodig S. J., Chirieac L. R., Kwak E. L., Lynch T. J., Lafrate A. J., 2009. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J. Clin. Oncol., 27(26): 4247−4253.

Shi Y., Au J. S., Thongprasert S., Srinivasan S., Tsai C. M., Khoa M. T., Heeroma K., Itoh Y., Cornelio G., Yang P. C., 2014. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J. Thorar. Oncol., 9(2): 154−162.

Soda M., Choi Y. L., Enomoto M., Takada S., Yamashita Y., Ishikawa S., Fujiwara S., Watanabe H., Kurashina K., Hatanaka H., Bando M., Ohno S., Ishikawa Y., Aburatani H., Niki T., Sohara Y., Sugiyama Y., Mano H., 2007. Identification of the transforming EMLA4-ALK fusion gen in non-small-cell lung cancer. Nature., 448(7153): 561−566.

Solomon B. J., Mok T., Kim D. W., Wu Y. L., Nakagawa K., Mekhail T., Felip E., Cappuzzo F., Paolini J., Usari T., Lyer S., Reisman A., Wilner K. D., Tursi J., Blackhall F., PROFILE 1014 Investigators, 2014. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med., 371(23): 2167−2177.

Suh J. H., Johnson A., Albacker L., Wang K., Chmielecki J., Frampton G., Gay L., Elvin J. A., Vergilio J. A., Ali S., Miller V. A., Stephens P. J., Ross J. S., 2016. Comprehensive genomic profiling facilitates implementation of the national comprehensive cancer network guidelines for lung cancer biomarker testing and identifies patients who may benefit from enrollment in mechanism-driven clinical trials. Oncologist., 21(6): 684−691.

Sun Y., Ren Y., Fang Z., Li C., Fang R., Gao B., Han X., Tian W., Pao W., Chen H., Ji H., 2010. Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. J. Clin. Oncol., 28(30): 4616−4620.

Takahashi M., Ritz J and Cooper G. M., 1985. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell., 42(2): 581−588.

Takeuchi K., Soda M., Togashi Y., Suzuki R., Sakata S., Hatano S., Asaka R., Hamanaka W., Ninomiya H., Uehara H., Lim Choi Y., Satoh Y., Okumura S., Nakagama K., Mano H., Ishikawa Y., 2012. RET, ROS1 and ALK fusions in lung cancer. Nat. Med., 18(3): 378−381.

Toyokawa G and Seto T., 2015. Updated evidence on the mechanisms of resistance to ALK inhibitor and strategies to overcome such resistance: Clinical and preclinical data. Oncol. Res. Treat., 38(6): 291−298.

Travis W. D., Brambilla E., Riely G. J., 2013. New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J. Clin. Oncol., 31(8): 992−1001.

Vogel W., Gish G. D., Alves F., Pawson T., 1997. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol. Cell., 1(1): 13−23.

Vuong H. G., Ho A. T. N., Altibi A. M. A., Nakazawa T., Katoh R., Kondo T., 2018. Clinicalpathological implications of MET exon 14 mutations in non-small cell lung cancer - A systematic review and meta-analysis. Lung Cancer., 123: 76−82.

Walsh L. A., Nawshad A., Medici D., 2011. Discoidin domain receptor 2 is a critical regulator of epithemial-mesenchymal transition. Matrix. Biol., 30(4): 243−247.

Yarden Y and Sliwkowski M. X., 2001. Untangling the erbB signaling network. Nat. Rev. Mol. Cell. Biol., 2(2): 127−137.

Yoh K., Seto T., Satouchi M., Nishio M., Yamamoto N., Murakami H., Nogami N., Matsumoto S., Kohno T., Tsuta K., Tschihara K., Ishii G., Nomura S., Sato A., Ohtsu A., Ohe Y., Goto K., 2017. Vandetanib in patients with previously treated RET-rearranged advanced non-small-cell lung cancer (LURET): an open-label, multicentre phase 2 trial. Lancet. Respir. Med., 5(1): 42−50.

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