biostudies-literatureKato SNCINCI NIH HHSNIH2792-2797https://www.ebi.ac.uk/biostudies/studies/S-EPMC11005753biostudies-literatureUnknown27(10)<h4>Purpose</h4>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.<h4>Experimental design</h4>Herein, we describe 9 patients with advanced malignancies harboring concomitant <i>CDKN2A</i> and/or <i>CDKN2B</i> alterations (upregulate CDK4/6) along with <i>KRAS</i> or <i>BRAF</i> alterations (activate the MEK pathway) who were treated with palbociclib (CDK4/6 inhibitor) and trametinib (MEK Clinical cancer research : an official journal of the American Association for Cancer ResearchConcomitant MEK and Cyclin Gene Alterations: Implications for Response to Targeted Therapeutics.PMC11005753K08 CA168999R21 CA192072K08CA168999P30 CA023100R21CA192072Okamura RLee SShaya JSicklick JKKurzrock RJimenez REKato SAdashek JJfalseConcomitant MEK and Cyclin Gene Alterations: Implications for Response to Targeted Therapeutics.<h4>Purpose</h4>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.<h4>Experimental design</h4>Herein, we describe 9 patients with advanced malignancies harboring concomitant <i>CDKN2A</i> and/or <i>CDKN2B</i> alterations (upregulate CDK4/6) along with <i>KRAS</i> or <i>BRAF</i> alterations (activate the MEK pathway) who were treated with palbociclib (CDK4/6 inhibitor) and trametinib (MEK 2021-01-01T00:00:00Z2021 May2026-05-29T17:44:58.355Z2026-04-08T05:41:23.68ZS-EPMC110057533347291010.1158/1078-0432.CCR-20-376110.1158/1078-0432.ccr-20-3761