Activation of RAS family members confers resistance to ROS1 targeting drugs

Cargnelutti, Marilisa; Corso, Simona; Pergolizzi, Margherita; Mévellec, Laurence; Aisner, Dara L.; Dziadziuszko, Rafał; Varella‐Garcia, Marileila; Comoglio, Paolo M.; Doebele, Robert C.; Vialard, Jorge; Giordano, Silvia

doi:10.18632/oncotarget.3311

Cited by 75 publications

(50 citation statements)

References 37 publications

(45 reference statements)

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“…In the search for resistance mechanisms in cell lines, a switch in signaling from ROS1 to EGFR was observed, when ROS1 was inhibited by crizotinib [74]. The same study [76] also reported that treatment with an EGFR inhibitor in combination with a ROS1 inhibitor was effective in cell lines resistant to ROS1 inhibitors. In another study, a new mutation, L2155S, was found in a ROS1-positive NSCLC cell line resistant to crizotinib.…”

Section: Mechanisms Of Resistance To Ros1 Inhibitorsmentioning

confidence: 97%

Genomic aberrations guiding treatment of non-small cell lung cancer patients

Saber

Wekken

Hiltermann

et al. 2015

Cancer Treatment Communications

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Lung cancer is the main cause of cancer-related death worldwide and conventional treatment strategies must be improved. In addition to mutations in several well-known cancer-associated genes, recent advances in sequencing technology have led to the discovery of numerous novel gene mutations and translocations. Some of these genomic aberrations occur at similar frequencies in all lung cancer subtypes, whereas others appear to be specific for adenocarcinoma or squamous cell lung cancer. High frequency mutations or recurrent translocations support involvement of the affected genes in the pathogenesis of lung cancer. The presence of activating aberrations is indicative for putative driver genes that might be essential for tumor cell growth and survival. These driver genes are potential targets for developing new treatments for lung cancer patients. Indeed, multiple tyrosine kinase inhibitors (TKIs) are currently used to treat lung cancer patients based on the presence of activating mutations, and novel drugs are under investigation. Patients benefit for about one year from current targeted treatments, but progression of disease inevitably occurs and resistance of the tumor to the TKI used can be observed in re-biopsied tumor samples. The aim of this review is to provide an overview of mutated genes in non-small cell lung cancer, an overview of targeted treatment strategies that are currently applied, and the known resistance mechanisms.

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Section: Mechanisms Of Resistance To Ros1 Inhibitorsmentioning

confidence: 97%

Genomic aberrations guiding treatment of non-small cell lung cancer patients

Saber

Wekken

Hiltermann

et al. 2015

Cancer Treatment Communications

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“…Reactivation of the MAPK pathway via either KRAS copy number gain or decreased expression of the MAPK phosphatase DUSP6 was associated with resistance to ALK inhibitors in patients with EML4-ALK-rearranged lung adenocarcinoma (38). Furthermore, activation of members of the RAS family was shown to confer resistance to ROS1 inhibitors (39). In EGFR-mutant lung cancers, resistance to EGFR TKIs may be associated with increased dependency on RAS-MAPK signaling, including ERK activation, loss of NF1, and CRKL amplification (13,(40)(41)(42).…”

Section: T790mmentioning

confidence: 98%

Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors

Ortiz-Cuarán

Scheffler

Plenker

et al. 2016

Clinical Cancer Research

222

194

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Purpose: To identify novel mechanisms of resistance to thirdgeneration EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).Experimental Design: We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.Results: We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRAS G12S mutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS.Conclusions: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies.

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“…Generally, KRAS, NRAS, BRAF, and MEK1 mutations do not occur concurrently with EGFR-or ALKactivating mutations, but such mutations have been reported in acquired resistance. KRAS mutations have been detected in EGFR TKI-resistant patient samples using more sensitive methods and in ALK-or ROS1-resistant patients (61,102,103).…”

Section: Bypass Pathwaysmentioning

confidence: 99%

“…This includes MAPK amplification or downregulation of neurofibromin 1 (NF1), which inactivates a Ras-activating GTPase in EGFR resistance; downregulation of the enzyme dual-specificity phosphatase 6 (DUSP6), which inactivates the pathway's tyrosine kinases in ALK-resistant cells; and KRAS amplification in ROS1 (103)(104)(105)(106). In BRAF V600 -mutant NSCLC, a truncated variant induced resistance to inhibition, but was able to maintain pathway signaling (107).…”

Section: Bypass Pathwaysmentioning

confidence: 99%