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Ref Type Journal Article
PMID (33472910)
Authors Kato S, Adashek JJ, Shaya J, Okamura R, Jimenez RE, Lee S, Sicklick JK, Kurzrock R
Title Concomitant MEK and Cyclin Gene Alterations: Implications for Response to Targeted Therapeutics.
Abstract Text Cyclin and MAPK/MEK-related gene alterations are implicated in cell-cycle progression and cancer growth. Yet, monotherapy to target the cyclin (CDK4/6) or the MEK pathway has often yielded disappointing results. Because coalterations in cyclin and MEK pathway genes frequently cooccur, we hypothesized that resistance to CDK4/6 or MEK inhibitor monotherapy might be mediated via activation of oncogenic codrivers, and that combination therapy might be useful.Herein, we describe 9 patients with advanced malignancies harboring concomitant CDKN2A and/or CDKN2B alterations (upregulate CDK4/6) along with KRAS or BRAF alterations (activate the MEK pathway) who were treated with palbociclib (CDK4/6 inhibitor) and trametinib (MEK inhibitor) combination-based regimens.Two patients (with pancreatic cancer) achieved a partial remission (PR) and, overall, 5 patients (56%) had clinical benefit (stable disease ≥ 6 months/PR) with progression-free survival of approximately 7, 9, 9, 11, and 17.5+ months. Interestingly, 1 of these patients whose cancer (gastrointestinal stromal tumor) had progressed on MEK targeting regimen, did well for about 1 year after palbociclib was added.These observations suggest that cotargeting cyclin and MEK signaling can be successful when tumors bear genomic coalterations that activate both of these pathways. Further prospective studies using this matching precision strategy to overcome resistance are warranted.See related commentary by Groisberg and Subbiah, p. 2672.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E CDKN2A R80* rhabdomyosarcoma predicted - sensitive Dabrafenib + Palbociclib + Trametinib Case Reports/Case Series Actionable In a clinical case study, the combination of Tafinlar (dabrafenib), Ibrance (palbociclib), and Mekinist (trametinib) resulted in a progression-free survival of 9 months in a patient with rhabdomyosarcoma harboring BRAF V600E and CDKN2A R80* (PMID: 33472910). 33472910