Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

  • Cancer Res. 2020 Nov 1;80(21):4840-4853. doi: 10.1158/0008-5472.CAN-20-1634.
Yuting Sun  1 ,  Brooke A Meyers  2 ,  Barbara Czako  3 ,  Paul Leonard  3 ,  Faika Mseeh  3 ,  Angela L Harris  2 ,  Qi Wu  3 ,  Sarah Johnson  2 ,  Connor A Parker  3 ,  Jason B Cross  3 ,  Maria Emilia Di Francesco  3 ,  Benjamin J Bivona  2 ,  Christopher A Bristow  2 ,  Jason P Burke  3 ,  Caroline C Carrillo  2 ,  Christopher L Carroll  3 ,  Qing Chang  2 ,  Ningping Feng  2 ,  Guang Gao  2 ,  Sonal Gera  2 ,  Virginia Giuliani  2 ,  Justin K Huang  2 ,  Yongying Jiang  3 ,  Zhijun Kang  3 ,  Jeffrey J Kovacs  2 ,  Chiu-Yi Liu  2 ,  Anastasia M Lopez  2 ,  Xiaoyan Ma  2 ,  Pijus K Mandal  3 ,  Timothy McAfoos  3 ,  Meredith A Miller  2 ,  Robert A Mullinax  2 ,  Michael Peoples  2 ,  Vandhana Ramamoorthy  2 ,  Sahil Seth  2 ,  Nakia D Spencer  2 ,  Erika Suzuki  2 ,  Christopher C Williams  3 ,  Simon S Yu  3 ,  Andy M Zuniga  2 ,  Giulio F Draetta  4 ,  Joseph R Marszalek  2 ,  Timothy P Heffernan  2 ,  Nancy E Kohl  5 ,  Philip Jones  3
Affiliations
  • 1. TRACTION - Translational Research to AdvanCe Therapeutics and Innovation in ONcology, The University of Texas MD Anderson Cancer Center, Houston, Texas. [email protected].
  • 2. TRACTION - Translational Research to AdvanCe Therapeutics and Innovation in ONcology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3. Institute for Applied Cancer Science (IACS), The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 4. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 5. Navire Pharma, San Francisco, California.
PMID: 32928921 DOI: 10.1158/0008-5472.CAN-20-1634
Abstract

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. SIGNIFICANCE: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

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