2. Academic Validation
  3. Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib

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

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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