Data from TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRAS<sup>G12C</sup> Inhibitors

Abstract

<div>Abstract<p>Primary/intrinsic and treatment-induced acquired resistance limit the initial response rate to and long-term efficacy of direct inhibitors of the KRAS<sup>G12C</sup> mutant in cancer. To identify potential mechanisms of resistance, we applied a CRISPR/Cas9 loss-of-function screen and observed loss of multiple components of the Hippo tumor suppressor pathway, which acts to suppress YAP1/TAZ-regulated gene transcription. YAP1/TAZ activation impaired the antiproliferative and proapoptotic effects of KRAS<sup>G12C</sup> inhibitor (G12Ci) treatment in <i>KRAS<sup>G12C</sup></i>-mutant cancer cell lines. Conversely, genetic suppression of <i>YAP1/WWTR1</i> (TAZ) enhanced G12Ci sensitivity. YAP1/TAZ activity overcame KRAS dependency through two distinct TEAD transcription factor–dependent mechanisms, which phenocopy KRAS effector signaling. First, TEAD stimulated ERK-independent transcription of genes normally regulated by ERK (<i>BIRC5</i>, <i>CDC20, ECT2, FOSL1</i>, and <i>MYC</i>) to promote progression through the cell cycle. Second, TEAD caused activation of PI3K–AKT–mTOR signaling to overcome apoptosis. G12Ci treatment-induced acquired resistance was also caused by YAP1/TAZ-TEAD activation. Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRAS<sup>G12C</sup> inhibitor antitumor activity <i>in vitro</i> and prolonged tumor suppression <i>in vivo</i>. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the antitumor efficacy of KRAS-targeted therapies.</p>Significance:<p>YAP1/TAZ-TEAD activation compensates for loss of KRAS effector signaling, establishing a mechanistic basis for concurrent inhibition of TEAD to enhance the efficacy of KRAS<sup>G12C</sup>-selective inhibitor treatment of <i>KRAS<sup>G12C</sup></i>-mutant cancers.</p><p><i><a href="https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-23-3547" target="_blank">See related commentary by Johnson and Haigis, p. 4005</a></i></p></div>