1. Academic Validation
  2. KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy

KRASG12C-independent feedback activation of wild-type RAS constrains KRASG12C inhibitor efficacy

  • Cell Rep. 2022 Jun 21;39(12):110993. doi: 10.1016/j.celrep.2022.110993.
Meagan B Ryan 1 Oluwadara Coker 2 Alexey Sorokin 2 Katerina Fella 1 Haley Barnes 1 Edmond Wong 1 Preeti Kanikarla 2 Fengqin Gao 2 Youyan Zhang 3 Lian Zhou 3 Scott Kopetz 2 Ryan B Corcoran 4
Affiliations

Affiliations

  • 1 Massachusetts General Hospital Cancer Center, 149 13(th) Street, 7(th) Floor, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 2 The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3 Eli Lilly, Indianapolis, IN, USA.
  • 4 Massachusetts General Hospital Cancer Center, 149 13(th) Street, 7(th) Floor, Boston, MA 02129, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: rbcorcoran@partners.org.
Abstract

Although KRAS has long been considered undruggable, direct KRASG12C inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and Others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear. We find that upstream feedback activation of wild-type Ras, as opposed to a shift in KRASG12C to its active guanosine triphosphate (GTP)-bound state, is sufficient to drive RAS-MAPK reactivation in a KRASG12C-independent manner. Moreover, multiple Receptor Tyrosine Kinases (RTKs) can drive feedback reactivation, potentially necessitating targeting of convergent signaling nodes for more universal efficacy. Even in colorectal Cancer, where feedback is thought to be primarily epidermal growth factor receptor (EGFR)-mediated, alternative RTKs drive pathway reactivation and limit efficacy, but convergent upstream or downstream signal blockade can enhance activity. Overall, these data provide important mechanistic insight to guide therapeutic strategies targeting KRAS.

Keywords

CP: Cancer; KRAS; KRASG12C; adagrasib; adaptive resistance; sotorasib.

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