ERK Inhibitor LY3214996-Based Treatment Strategies for<i>RAS</i>-Driven Lung Cancer

Köhler, Jens; Zhao, Yutong; Li, Jiaqi; Gokhale, Prafulla C.; Tiv, Hong L.; Knott, Aine; Wilkens, Margaret K.; Soroko, Kara M.; Lin, Mika; Ambrogio, Chiara; Musteanu, Mónica; Ogino, Atsuko; Choi, Jihyun; Bahcall, Magda; Bertram, Arrien A.; Chambers, Emily S.; Paweletz, Cloud P.; Bhagwat, Shripad V.; Manro, Jason R.; Tiu, Ramon V.

doi:10.1158/1535-7163.mct-20-0531

Cited by 21 publications

(15 citation statements)

References 66 publications

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“…PI3K pathway inhibitors are more suitable as an option in combination therapy for KRAS -mutant cancers, because there are overlapping feedback mechanisms between the MAPK and PI3K pathways, meaning that inhibition of one pathway can result in the compensatory activation of the other [ 111 , 117 , 118 ]. Therefore, the combination of MAPK and PI3K inhibitors may be a compelling regimen for the treatment of KRAS -mutant cancers.…”

Section: Kras Targeting Therapy In Crcmentioning

confidence: 99%

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

et al. 2021

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Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

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Section: Kras Targeting Therapy In Crcmentioning

confidence: 99%

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

et al. 2021

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“…ERK inhibitors (ERKi) have not been studied as widely as RAF and MEK inhibitors; however, ERK inhibitors have entered clinical trials in recent years. Recent preclinical research was performed on seven different RAS mutant patient-derived xenograft (PDX) models with LY3214996, a competitive ERK1/2 inhibitor [39]. While the MAPK inhibition levels were similar across the models, the actual tumor regression varied, suggesting that potential compensatory resistance mechanisms develop under ERK inhibition [39].…”

Section: Erk Inhibitorsmentioning

confidence: 99%

“…Recent preclinical research was performed on seven different RAS mutant patient-derived xenograft (PDX) models with LY3214996, a competitive ERK1/2 inhibitor [39]. While the MAPK inhibition levels were similar across the models, the actual tumor regression varied, suggesting that potential compensatory resistance mechanisms develop under ERK inhibition [39]. The ERK inhibitor MK-8352 (the oral derivative of tool compound SCH-772984) showed preclinical evidence of reduced ERK phosphorylation, a decrease in cell proliferation, and increased apoptosis in RAS mutant models.…”

Section: Erk Inhibitorsmentioning

confidence: 99%

Clinical Translation of Combined MAPK and Autophagy Inhibition in RAS Mutant Cancer

Lee

Jain

Amaravadi

2021

IJMS

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RAS (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including RAS, RAF, MEK, and ERK, have demonstrated activity in BRAF mutant and, in limited cases, RAS mutant cancer. RAS mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to RAS mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.

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“…Hence, for a long time, cytotoxic chemotherapy remained the mainstay of treatment that could achieve some, but mostly short-lived, tumor control [8,54]. Therapeutic efforts have recently focused more on ERK inhibitors (e.g., GDC0994 or LY3214996) or ERK-inhibitor-based drug combinations (e.g., combined with PI3K/mTOR or CDK4/6 inhibitors), since ERK1/2 proteins are considered to have a bottleneck function in transmitting mitogenic signals and preventing MAPK pathway feedback reactivation [65][66][67][68]. These drug combinations are effective in preclinical models if applied on intermittent treatment schedules, but future clinical trials will have to clarify if this approach can overcome therapeutic limitations and toxicities observed with continuous MEK inhibition.…”

Section: Kras-mutant Nsclc: Therapeutically Challenging With a Plethomentioning

confidence: 99%

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

Köhler

2021

IJMS

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Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.

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ERK Inhibitor LY3214996-Based Treatment Strategies forRAS-Driven Lung Cancer

Cited by 21 publications

References 66 publications

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer

Clinical Translation of Combined MAPK and Autophagy Inhibition in RAS Mutant Cancer

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

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