Repurposing EGFR Inhibitor Utility in Colorectal Cancer in Mutant and Subpopulations

Overview

Journal Cancer Epidemiol Biomarkers Prev

Specialties Biochemistry
Oncology
Public Health

Date 2019 Apr 25

PMID 31015202

Citations 14

Authors

Mingli Yang

Michael J Schell

Andrey Loboda

Michael Nebozhyn

Jiannong Li

Jamie K Teer

W Jack Pledger

Timothy J Yeatman

Affiliations

Soon will be listed here.

Abstract

Background: EGFR is a major therapeutic target for colorectal cancer. Currently, extended testing identifies only nonresponders to EGFR inhibitors (EGFRi). We aimed to develop a mutation signature that further refines drug-sensitive subpopulations to improve EGFRi outcomes.

Methods: A prespecified, 203-gene expression signature score measuring cetuximab sensitivity (CTX-S) was validated with two independent clinical trial datasets of cetuximab-treated patients with colorectal cancer ( = 44 and = 80) as well as an dataset of 147 cell lines. The CTX-S score was then used to decipher mutated genes that predict EGFRi sensitivity. The predictive value of the identified mutation signature was further validated by additional independent datasets.

Results: Here, we report the discovery of a 2-gene (+) mutation signature that was useful in identifying EGFRi-sensitive colorectal cancer subpopulations. Mutant + tumors were more predominant in left- versus right-sided colorectal cancers (52% vs. 21%, = 0.0004), in microsatellite stable (MSS) versus microsatellite instable (MSI) cases (47% vs. 2%, < 0.0001), and in the consensus molecular subtype 2 versus others (75% vs. 37%, < 0.0001). Moreover, mutant + tumors had favorable outcomes in two cetuximab-treated patient-derived tumor xenograft (PDX) datasets ( = 0.0277, = 52; = 0.0008, = 98).

Conclusions: Our findings suggest that the and combination mutation may account for the laterality of EGFRi sensitivity and provide a rationale for refining treated populations. The results also suggest addition of + sequencing to extended testing that may directly increase the response rates of EGFRi therapy in selected patients.

Impact: These findings, if further validated through clinical trials, could also expand the utility of EGFRi therapies that are currently underutilized.

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References

Sauer L, Gitenay D, Vo C, Baron V . Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells. Oncogene. 2010; 29(18):2628-37. PMC: 2865566. DOI: 10.1038/onc.2010.24. View

Okita A, Takahashi S, Ouchi K, Inoue M, Watanabe M, Endo M . Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. Oncotarget. 2018; 9(27):18698-18711. PMC: 5922348. DOI: 10.18632/oncotarget.24617. View

Stintzing S, Miller-Phillips L, Modest D, Fischer von Weikersthal L, Decker T, Kiani A . Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study. Eur J Cancer. 2017; 79:50-60. DOI: 10.1016/j.ejca.2017.03.023. View

Mosakhani N, Lahti L, Borze I, Karjalainen-Lindsberg M, Sundstrom J, Ristamaki R . MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF. Cancer Genet. 2012; 205(11):545-51. DOI: 10.1016/j.cancergen.2012.08.003. View

Hecht J, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D . A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2008; 27(5):672-80. DOI: 10.1200/JCO.2008.19.8135. View

Medico E, Russo M, Picco G, Cancelliere C, Valtorta E, Corti G . The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets. Nat Commun. 2015; 6:7002. DOI: 10.1038/ncomms8002. View

Davis T, Yang M, Schell M, Wang H, Ma L, Pledger W . PTPRS Regulates Colorectal Cancer RAS Pathway Activity by Inactivating Erk and Preventing Its Nuclear Translocation. Sci Rep. 2018; 8(1):9296. PMC: 6006154. DOI: 10.1038/s41598-018-27584-x. View

Schell M, Yang M, Teer J, Lo F, Madan A, Coppola D . A multigene mutation classification of 468 colorectal cancers reveals a prognostic role for APC. Nat Commun. 2016; 7:11743. PMC: 4912618. DOI: 10.1038/ncomms11743. View

Pentheroudakis G, Kotoula V, De Roock W, Kouvatseas G, Papakostas P, Makatsoris T . Biomarkers of benefit from cetuximab-based therapy in metastatic colorectal cancer: interaction of EGFR ligand expression with RAS/RAF, PIK3CA genotypes. BMC Cancer. 2013; 13:49. PMC: 3599697. DOI: 10.1186/1471-2407-13-49. View

10.

Giannakis M, Mu X, Shukla S, Qian Z, Cohen O, Nishihara R . Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep. 2016; 15(4):857-865. PMC: 4850357. DOI: 10.1016/j.celrep.2016.03.075. View

11.

Modest D, Stintzing S, Fischer von Weikersthal L, Decker T, Kiani A, Vehling-Kaiser U . Exploring the effect of primary tumor sidedness on therapeutic efficacy across treatment lines in patients with metastatic colorectal cancer: analysis of FIRE-3 (AIOKRK0306). Oncotarget. 2017; 8(62):105749-105760. PMC: 5739676. DOI: 10.18632/oncotarget.22396. View

12.

Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F . Prognostic and Predictive Relevance of Primary Tumor Location in Patients With RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses of the CRYSTAL and FIRE-3 Trials. JAMA Oncol. 2016; 3(2):194-201. PMC: 7505121. DOI: 10.1001/jamaoncol.2016.3797. View

13.

Lee C, McCarthy S, Gruidl M, Timme C, Yeatman T . MicroRNA-147 induces a mesenchymal-to-epithelial transition (MET) and reverses EGFR inhibitor resistance. PLoS One. 2014; 9(1):e84597. PMC: 3893127. DOI: 10.1371/journal.pone.0084597. View

14.

Douillard J, Oliner K, Siena S, Tabernero J, Burkes R, Barugel M . Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013; 369(11):1023-34. DOI: 10.1056/NEJMoa1305275. View

15.

Holch J, Ricard I, Stintzing S, Modest D, Heinemann V . The relevance of primary tumour location in patients with metastatic colorectal cancer: A meta-analysis of first-line clinical trials. Eur J Cancer. 2016; 70:87-98. DOI: 10.1016/j.ejca.2016.10.007. View

16.

Modest D, Jung A, Moosmann N, Laubender R, Giessen C, Schulz C . The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial. Int J Cancer. 2011; 131(4):980-6. DOI: 10.1002/ijc.26467. View

17.

Weickhardt A, Price T, Chong G, Gebski V, Pavlakis N, Johns T . Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. J Clin Oncol. 2012; 30(13):1505-12. DOI: 10.1200/JCO.2011.38.6599. View

18.

Marisa L, De Reynies A, Duval A, Selves J, Gaub M, Vescovo L . Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med. 2013; 10(5):e1001453. PMC: 3660251. DOI: 10.1371/journal.pmed.1001453. View

19.

Guinney J, Dienstmann R, Wang X, De Reynies A, Schlicker A, Soneson C . The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21(11):1350-6. PMC: 4636487. DOI: 10.1038/nm.3967. View

20.

De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G . Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010; 11(8):753-62. DOI: 10.1016/S1470-2045(10)70130-3. View