EGFR fusions as novel therapeutic targets in lung cancer

Kartik Konduri; Jean Nicolas Gallant; Young Kwang Chae; Francis J. Giles; Barbara J. Gitlitz; Kyle Gowen; Eiki Ichihara; Taofeek K. Owonikoko; Vijay Peddareddigari; Suresh S. Ramalingam; Satyanarayan K. Reddy; Beth Eaby-Sandy; Tiziana Vavalà; Andrew Whiteley; Heidi Chen; Yingjun Yan; Jonathan H. Sheehan; Jens Meiler; Deborah Morosini; Jeffrey S. Ross; Philip J. Stephens; Vincent A. Miller; Siraj M. Ali; Christine M. Lovly

doi:10.1158/2159-8290.CD-16-0075

EGFR fusions as novel therapeutic targets in lung cancer

Kartik Konduri, Jean Nicolas Gallant, Young Kwang Chae, Francis J. Giles, Barbara J. Gitlitz, Kyle Gowen, Eiki Ichihara, Taofeek K. Owonikoko, Vijay Peddareddigari, Suresh S. Ramalingam, Satyanarayan K. Reddy, Beth Eaby-Sandy, Tiziana Vavalà, Andrew Whiteley, Heidi Chen, Yingjun Yan, Jonathan H. Sheehan, Jens Meiler, Deborah Morosini, Jeffrey S. RossPhilip J. Stephens, Vincent A. Miller, Siraj M. Ali, Christine M. Lovly^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

108 Scopus citations

Abstract

Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration. SIGNIFICANCE: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors.

Original language	English (US)
Pages (from-to)	601-611
Number of pages	11
Journal	Cancer discovery
Volume	6
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-16-0075
State	Published - Jun 2016

Funding

The authors thank the patients and their families. They are grateful to William Pao and Catherine Meador for critical review of the manuscript. Grant Support This study was supported in part by the NIH and NCI R01CA121210 (C.M. Lovly) and P01CA129243. Research was supported by the 2015 AACR-Genentech BioOncology Career Development Award for Cancer Research on the HER Family Pathway, grant number 15-2018-LOVL (to C.M. Lovly). C.M. Lovly, J.-N. Gallant, and J.H. Sheehan were supported by a V Foundation Scholar-in-Training Award. C.M. Lovly was additionally supported by a Damon Runyon Clinical Investigator Award and a LUNGevity Career Development Award. J.-N. Gallant was additionally supported by F30CA206339 and MSTP grant T32GM007347. Work in the Meiler laboratory is supported through the NIH (R01GM080403, R01GM099842, R01DK097376, R01HL122010, and R01GM073151) and the NSF (CHE1305874). T. Vavalà and B.J. Gitlitz were part of the Genomic of Young Lung Cancer study (GoYLC; NCT02273336), which was funded by the Bonnie J. Addario Lung Cancer Foundation, the Peter Barker Foundation, Genentech, the Beth Longwell Foundation, the Schmidt Legacy Foundation, and Upstage Lung Cancer.

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-16-0075

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Konduri, K., Gallant, J. N., Chae, Y. K., Giles, F. J., Gitlitz, B. J., Gowen, K., Ichihara, E., Owonikoko, T. K., Peddareddigari, V., Ramalingam, S. S., Reddy, S. K., Eaby-Sandy, B., Vavalà, T., Whiteley, A., Chen, H., Yan, Y., Sheehan, J. H., Meiler, J., Morosini, D., ... Lovly, C. M. (2016). EGFR fusions as novel therapeutic targets in lung cancer. Cancer discovery, 6(6), 601-611. https://doi.org/10.1158/2159-8290.CD-16-0075

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title = "EGFR fusions as novel therapeutic targets in lung cancer",

abstract = "Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration. SIGNIFICANCE: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors.",

author = "Kartik Konduri and Gallant, \{Jean Nicolas\} and Chae, \{Young Kwang\} and Giles, \{Francis J.\} and Gitlitz, \{Barbara J.\} and Kyle Gowen and Eiki Ichihara and Owonikoko, \{Taofeek K.\} and Vijay Peddareddigari and Ramalingam, \{Suresh S.\} and Reddy, \{Satyanarayan K.\} and Beth Eaby-Sandy and Tiziana Vaval{\`a} and Andrew Whiteley and Heidi Chen and Yingjun Yan and Sheehan, \{Jonathan H.\} and Jens Meiler and Deborah Morosini and Ross, \{Jeffrey S.\} and Stephens, \{Philip J.\} and Miller, \{Vincent A.\} and Ali, \{Siraj M.\} and Lovly, \{Christine M.\}",

note = "Publisher Copyright: {\textcopyright} 2016 American Association for Cancer Research.",

year = "2016",

month = jun,

doi = "10.1158/2159-8290.CD-16-0075",

language = "English (US)",

volume = "6",

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journal = "Cancer discovery",

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Konduri, K, Gallant, JN, Chae, YK, Giles, FJ, Gitlitz, BJ, Gowen, K, Ichihara, E, Owonikoko, TK, Peddareddigari, V, Ramalingam, SS, Reddy, SK, Eaby-Sandy, B, Vavalà, T, Whiteley, A, Chen, H, Yan, Y, Sheehan, JH, Meiler, J, Morosini, D, Ross, JS, Stephens, PJ, Miller, VA, Ali, SM & Lovly, CM 2016, 'EGFR fusions as novel therapeutic targets in lung cancer', Cancer discovery, vol. 6, no. 6, pp. 601-611. https://doi.org/10.1158/2159-8290.CD-16-0075

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AU - Konduri, Kartik

AU - Gallant, Jean Nicolas

AU - Chae, Young Kwang

AU - Giles, Francis J.

AU - Gitlitz, Barbara J.

AU - Gowen, Kyle

AU - Ichihara, Eiki

AU - Owonikoko, Taofeek K.

AU - Peddareddigari, Vijay

AU - Ramalingam, Suresh S.

AU - Reddy, Satyanarayan K.

AU - Eaby-Sandy, Beth

AU - Vavalà, Tiziana

AU - Whiteley, Andrew

AU - Chen, Heidi

AU - Yan, Yingjun

AU - Sheehan, Jonathan H.

AU - Meiler, Jens

AU - Morosini, Deborah

AU - Ross, Jeffrey S.

AU - Stephens, Philip J.

AU - Miller, Vincent A.

AU - Ali, Siraj M.

AU - Lovly, Christine M.

PY - 2016/6

Y1 - 2016/6

N2 - Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration. SIGNIFICANCE: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors.

AB - Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration. SIGNIFICANCE: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors.

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SN - 2159-8274

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JO - Cancer discovery

JF - Cancer discovery

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ER -

EGFR fusions as novel therapeutic targets in lung cancer

Abstract

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UN SDGs

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