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WO 2017/180581 Al 19 October 2017 (19.10.2017) P O P C T

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WO 2017/180581 Al 19 October 2017 (19.10.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/180581 Al 19 October 2017 (19.10.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, PCT/US20 17/026941 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, 11 April 2017 ( 11.04.2017) KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (25) Filing Language: English NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (26) Publication Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (30) Priority Data: ZA, ZM, ZW. 62/323,210 15 April 2016 (15.04.2016) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except AL, AT, BA, kind of regional protection available): ARIPO (BW, GH, BE, BG, CH, CN, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, NO, PL, P T RO, RS, SE, SI, SK, SM, TR) : GENENTECH, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, INC. [US/US]; 1 DNA Way, South San Francisco, CA DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 94080-4990 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (71) Applicant (for AL, AT, BA, BE, BG, CH, CN, CY, CZ, DE, GW, KM, ML, MR, NE, SN, TD, TG). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IN, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, Declarations under Rule 4.17 : SK SM, TR only): F. HOFFMANN-LA ROCHE AG — as to applicant's entitlement to apply for and be granted a [CH/CH]; Grenzacherstrasse 124, 4070 Basel (CH). patent (Rule 4.1 7(H)) (72) Inventors: KIROUAC, Daniel, Christopher; 1 DNA — as to the applicant's entitlement to claim the priority of the Way, South San Francisco, CA 9480-4990 (US). earlier application (Rule 4.1 7(in)) WAGLE, Marie-Claire; 1 DNA Way, South San Fran cisco, CA 94080-4990 (US). HUANG, Shih-Min; 1 DNA Published: Way, South San Francisco, CA 94080-4990 (US). — with international search report (Art. 21(3)) (74) Agent: ELBING, Karen, L.; Clark & Elbing LLP, 101 — with sequence listing part of description (Rule 5.2(a)) Federal Street, 15th Floor, Boston, MA 021 10 (US). 00 o o (54) Title: DIAGNOSTIC AND THERAPEUTIC METHODS FOR CANCER (57) Abstract: The present invention provides diagnostic and therapeutic methods and compositions for cancer. The invention provides methods of determining whether a patient having a cancer is likely to respond to treatment comprising a MAPK signaling inhibitor, methods of predicting responsiveness of a patient having a cancer to treatment comprising one or more MAPK signaling inhibitors, methods of selecting a therapy for a patient having a cancer, and methods of treating cancer based on expression levels of biomarkers of the invention (e.g., the expression levels of DUSP6, ETV4, SPRY2, SPRY4, PHLDAl, ETV5, DUSP4, CCNDl, EPHA2, and EPHA4). DIAGNOSTIC AND THERAPEUTIC METHODS FOR CANCER SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCI I format and is hereby incorporated by reference in its entirety. Said ASCI I copy, created on April 10 , 201 7 , is named 50474-1 33WO2_Sequence_Listing_4_1 0_1 7_ST25 and is 100,570 bytes in size. FIELD OF THE INVENTION The present invention is directed to diagnostic and therapeutic methods for the treatment of proliferative cell disorders (e.g. , cancers) using MAPK (e.g. , mitogen-activated protein kinase) signaling inhibitors. Also provided are related kits and compositions. BACKGROUND Cancer remains one of the most deadly threats to human health. Certain cancers can metastasize and grow rapidly in an uncontrolled manner, making timely detection and treatment extremely difficult. In the U.S., cancer affects nearly 1.3 million new patients each year and is the second leading cause of death after heart disease, accounting for approximately one in four deaths. The mitogen-activated protein kinase (MAPK) signaling pathway is activated in more than 30% of human cancers, most commonly in the MEK/ERK arm of the pathway via mutations in KRAS and/or in BRAF. RAS mutations occur with a frequency of 90% in pancreatic tumors, 35% in lung adenocarcinoma (non- small cell lung cancer (NSCLC)) tumors, 45% in colorectal tumors, and 15% in melanoma tumors. BRAF mutations occur in 66% of melanoma tumors and 12% of colorectal tumors. Tumors with KRAS mutations were predicted to be sensitive to MEK inhibition due to activation of MAPK signaling. However, MEK inhibitors in multiple clinical trials, either as a monotherapy or in combination with chemotherapies, have not shown superior efficacy in the KRAS mutant subgroup compared to the KRAS wild-type subgroup, indicating a limitation of utilizing KRAS mutation status as a predictive biomarker of MEK inhibitor sensitivity. In addition, stratification based on KRAS mutation status may inadvertently overlook wild-type KRAS tumors that could be addicted to MAPK signaling, independent of KRAS mutation status. Thus, there remains a need to develop improved alternative methods for diagnosing and treating patient populations best suited for treatment including one or more MAPK signaling inhibitors. SUMMARY OF THE INVENTION The present invention provides diagnostic and therapeutic methods, kits, and compositions for the treatment of proliferative cell disorders (e.g. , cancers). In a first aspect, the invention features a method of identifying a patient having a cancer who may benefit from treatment comprising one or more MAPK (mitogen-activated protein kinase) signaling inhibitors, the method comprising determining an expression level of at least one gene (e.g., one, two, three, four, five, six, seven, eight, nine, or ten genes) selected from the group consisting of DUSP6, ETV4, SPRY2, SPRY4, PHLDA1 , ETV5, DUSP4, CCN D 1 , EPHA2, and EPHA4 in a sample obtained from the patient, wherein an increased expression level of the at least one gene in the sample as compared to a reference level identifies the patient as one who may benefit from treatment comprising one or more MAPK signaling inhibitors. In a second aspect, the invention features a method of optimizing therapeutic efficacy for treatment of a patient having a cancer, the method comprising determining an expression level of at least one gene (e.g ., one, two, three, four, five, six, seven, eight, nine, or ten genes) selected from the group consisting of DUSP6, ETV4, SPRY2, SPRY4, PHLDA1 , ETV5, DUSP4, CCND1 , EPHA2, and EPHA4 in a sample obtained from the patient, wherein an increased expression level of the at least one gene in the sample as compared to a reference level indicates that the patient has an increased likelihood of benefiting from treatment comprising one or more MAPK signaling inhibitors. In a third aspect, the invention features a method of predicting responsiveness of a patient having a cancer to treatment comprising one or more MAPK signaling inhibitors, the method comprising determining an expression level of at least one gene (e.g. , one, two, three, four, five, six, seven, eight, nine, or ten genes) selected from the group consisting of DUSP6, ETV4, SPRY2, SPRY4, PHLDA1 , ETV5, DUSP4, CCND1 , EPHA2, and EPHA4 in a sample obtained from the patient, wherein an increased expression level of the at least one gene in the sample as compared to a reference level indicates that the patient has an increased likelihood of benefiting from treatment comprising one or more MAPK signaling inhibitors. In a fourth aspect, the invention features a method of selecting a treatment for a patient having a cancer, the method comprising determining an expression level of at least one gene (e.g. , one, two, three, four, five, six, seven, eight, nine, or ten genes) selected from the group consisting of DUSP6, ETV4, SPRY2, SPRY4, PHLDA1 , ETV5, DUSP4, CCN D 1 , EPHA2, and EPHA4 in a sample obtained from the patient, wherein an increased expression level of the at least one gene in the sample as compared to a reference level indicates that the patient has an increased likelihood of benefiting from treatment comprising one or more MAPK signaling inhibitors. In some embodiments of any one of the first, second, third, and fourth aspects, the method comprises determining the expression levels of at least four genes (e.g., four, five, six, seven, eight, nine, or ten genes) selected from DUSP6, ETV4, SPRY2, SPRY4, PHLDA1 , ETV5, DUSP4, CCND1 , EPHA2, and EPHA4. In some embodiments, the at least four genes comprise DUSP6, ETV4, SPRY2, and SPRY4. In other embodiments, the method comprises determining the expression levels of at least five genes selected from DUSP6, ETV4, SPRY2, SPRY4, PHLDA1 , ETV5, DUSP4, CCND1 , EPHA2, and EPHA4. In some embodiments, the at least five genes comprise DUSP6, ETV4, SPRY2, SPRY4, and PHLDA1 .
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