Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer

Abstract

NTRK1 gene fusions are actionable drivers of numerous human malignancies. Here, we show that expression of the TPR-NTRK1 fusion kinase in immortalized mouse pancreatic ductal epithelial (IMPE) (pancreas) or mouse lung epithelial (MLE-12) cells is sufficient to promote rapidly growing tumors in mice. Both tumor models are exquisitely sensitive to targeted inhibition with entrectinib, a tropomyosin-related kinase A (TRKA) inhibitor. Initial regression of NTRK1-driven tumors is driven by induced expression of BIM, such that BIM silencing leads to a diminished response to entrectinib in vivo. However, the emergence of drugresistant disease limits the long-term durability of responses. Based on the reactivation of RAF>MEK>ERK signaling observed in entrectinib-treated tumors, we show that the combination of entrectinib plus the MEK1/2 inhibitor cobimetinib dramatically forestalls the onset of drug resistance in vivo. Collectively, these data provide a mechanistic rationale for rapid clinical deployment of combined inhibition of TRKA plus MEK1/2 in NTRK1-driven cancers.

NTRK Fusion in Non-Small Cell Lung Cancer: Diagnosis, Therapy, and TRK Inhibitor Resistance

“…Off-target mechanisms can develop during TRK inhibitor treatment, which include genomic alterations of downstream pathway mediators and other receptor tyrosine kinases ( Figure 2 ). Preclinical study showed that the reactivation of RAF-MEK-ERK signaling was observed in NTRK1-driven pancreatic cancer and lung cancer treated with entrectinib, which was possibly one of the acquired-resistance mechanisms to entrectinib, and combined inhibition of TRKA plus MEK1/2 markedly forestalled the onset of drug resistance in both models ( 85 ). Furthermore, BRAF V600E mutation, KRAS G12D mutations, and MET amplifications were also identified as the bypass-mediated resistance mechanisms to TRK inhibitors for patients with NTRK fusions.…”

Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer

“…Understanding the factors underlying intrinsic/acquired resistance to this new class of compounds is critical, in particular for CRC patient benefit. There is a growing body of evidence suggesting that deficient apoptosis induction following targeted therapy treatments can lead to a lack of efficacy (37, 38). Indeed, we found that KRAS G12C inhibitor monotherapy was relatively ineffective at inducing apoptosis in vitro in KRAS G12C MT CRC.…”

Clinical Activity of Selitrectinib in a Patient With Mammary Analogue Secretory Carcinoma of the Parotid Gland With Secondary Resistance to Entrectinib

“…21 Silencing of BIM, downstream of the MAPK pathway, contributed to resistance to entrectinib in 2 new TPR-TRKA driven mice models in pancreatic and lung cancer. 22 In these models, vertical inhibition using entrectinib 1 cobimetinib (an MEK inhibitor) delayed the onset of resistance to entrectinib. Thus, upfront dual targeting of the implicated pathways may delay the emergence of resistant tumor clones and lead to more durable disease control compared with monotherapy.…”