Molecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer

Abstract

With the combination of KRAS G12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRAS G12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRAS G12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance.

Modulation of the proteostasis network promotes tumor resistance to oncogenic KRAS inhibitors

“…Recent studies report reactivated ERK and AKT as sotorasib-resistant mechanisms in patients (18,19,(21)(22)(23). We observed the reactivation of phospho-ERK and the hyperactivation of phospho-AKT in sotorasib-resistant MIA-PaCa-2 R and H358 R cells compared with their respective parental cells (Fig.…”

“…Next, we sought to understand the mechanism that activates ERK and AKT in the KRASiresistant cells. Receptor tyrosine kinases (RTKs) activation is one of the most common mechanisms driving sotorasib resistance in patients (20)(21)(22), and RTKs are known to activate ERK and AKT (17,19,30,80). Array analysis of 49 RTKs in parental and sotorasib-resistant H358 and MIA-PaCa-2 models revealed the induction of multiple and distinct sets of RTKs in each model (fig.…”

“…Although the simultaneous suppression of the MAPK and PI3K pathways, or diverse upstream RTKs, effectively inhibits IRE1a, the heterogeneous resistance mechanisms in different patients (18)(19)(20)(21)(22)(23) and dose-limiting, on-target toxicity of these inhibitors (81, 82) limit their clinical applications for intervening in IRE1amediated proteostasis reprogramming in treatment-resistant tumors. Therefore, we directly targeted the IRE1a/XBP1 pathway in KRAS-driven cancers in combination with KRAS G12C or MEK inhibitor.…”

Neutrophil extracellular traps in tumor progression and immunotherapy

“…Resistance to tumor includes both primary and secondary resistance. Targeted therapy is frequently associated with acquired resistance ( 106 ), whereas immunotherapy is often associated with primary resistance ( 107 ). In the area of malignancy, tumor-associated neutrophils (TANs) have been shown to contribute to cancer resistance to therapies ( 108 ).…”

KRAS: Druggable at Last

“… 22 , 23 Resistance patterns to adagrasib/cetuximab combination therapy also appear different than resistance to monotherapy, at least for colorectal cancers, and lead to unique biology when KRAS inhibitors are withdrawn. 24 These early data underscore the lesson that even common mutations can lead to very different biology in different histologies. With direct KRAS inhibitors, we have tools to rapidly innovate such strategies in near real-time to benefit patients.…”