TY - JOUR
T1 - Allosteric SHP2 inhibitor, IACS-13909, overcomes EGFR-dependent and EGFR-independent resistance mechanisms toward osimertinib
AU - Sun, Yuting
AU - Meyers, Brooke A.
AU - Czako, Barbara
AU - Leonard, Paul
AU - Mseeh, Faika
AU - Harris, Angela L.
AU - Wu, Qi
AU - Johnson, Sarah
AU - Parker, Connor A.
AU - Cross, Jason B.
AU - Di Francesco, Maria Emilia
AU - Bivona, Benjamin J.
AU - Bristow, Christopher A.
AU - Burke, Jason P.
AU - Carrillo, Caroline C.
AU - Carroll, Christopher L.
AU - Chang, Qing
AU - Feng, Ningping
AU - Gao, Guang
AU - Gera, Sonal
AU - Giuliani, Virginia
AU - Huang, Justin K.
AU - Jiang, Yongying
AU - Kang, Zhijun
AU - Kovacs, Jeffrey J.
AU - Liu, Chiu Yi
AU - Lopez, Anastasia M.
AU - Ma, Xiaoyan
AU - Mandal, Pijus K.
AU - McAfoos, Timothy
AU - Miller, Meredith A.
AU - Mullinax, Robert A.
AU - Peoples, Michael
AU - Ramamoorthy, Vandhana
AU - Seth, Sahil
AU - Spencer, Nakia D.
AU - Suzuki, Erika
AU - Williams, Christopher C.
AU - Yu, Simon S.
AU - Zuniga, Andy M.
AU - Draetta, Giulio F.
AU - Marszalek, Joseph R.
AU - Heffernan, Timothy P.
AU - Kohl, Nancy E.
AU - Jones, Philip
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC.
AB - Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non-small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC.
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UR - http://www.scopus.com/inward/citedby.url?scp=85097047599&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-1634
DO - 10.1158/0008-5472.CAN-20-1634
M3 - Article
C2 - 32928921
AN - SCOPUS:85097047599
SN - 0008-5472
VL - 80
SP - 4840
EP - 4853
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -