2014 YITA Research Project

Targeting YAP Signaling to Enhance Survival Across Molecular Subtypes of Non-Small Cell Lung Cancer (NSCLC).

2014 YITA Recipients

Trever Bivona, MD, PhD

Jonathan Reiss, MD

Ryan Corcoran, MD, PhD

After a rigorous, multi-level peer review of the submitted applications and in-person presentations to the ALCF Peer Review Committee composed of global lung cancer experts, the 2014 Bonnie J. Addario Lung Cancer Foundation – Van Auken Private Foundation Young Innovators Team Award has been awarded to a multidisciplinary, cross-institutional team comprised of Trever Bivona, MD, PhD (University of California, San Francisco); Jonathan Reiss, MD (University of California, Davis) and Ryan Corcoran, MD, PhD (Massachusetts General Hospital, Harvard Medical School).

2014 YITA Research Project Description

Under the 2014 YITA, Drs. Bivona, Reiss and Corcoran will evaluate a unique drug target in non-small cell lung cancer (NSCLC) that they have identified in preliminary studies to be active in 20-30% of all patients with NSCLC, and a potential cause for resistance to therapy. This drug target, the YAP/TAZ signaling pathway, is active in NSCLCs with the ‘undruggable’ RAS mutations. Interestingly, YAP/TAZ signaling is also active in a subset of EGFR mutant and ALK fusion positive NSCLC patients with acquired resistance to EGFR or ALK kinase inhibitors, and may therefore be a unique method to overcome treatment resistance in these patients as well. Therefore, targeting the YAP/TAZ signaling pathway has the potential for profound clinical impact by improving survival in NSCLC patients, including those in whom targeted therapy is not used or is ineffective.

With the ALCF-VAPF funding, Drs. Bivona, Reiss and Corcoran will 1) study the mechanism by which the YAP/TAZ signaling pathway promotes NSCLC survival and therapy resistance, 2) credential YAP/TAZ signaling as a new biomarker and target to enhance outcomes in NSCLC patients, 3) identify a YAP/TAZ targeted therapy for further clinical development. Based on the biological, molecular and clinical evidence generated from these studies, the results are likely to be translated into a ‘precision/ personalized medicine’ clinical trial for NSCLC patients to evaluate targeted therapy for these patients.

The 2014 YITA team will be under the guidance of their respective mentors at their own institutions: Kevin Shannon, MD (UCSF); David Gandara, MD (UC, Davis); Jeffrey Engelman, MD, PhD (Massachusetts General Hospital), as well as the ALCF YITA Scientific Review Committee comprised of: David Carbone, MD, PhD (The Ohio State University), David Gandara, MD (University of California, Davis), Roy Herbst, MD, PhD (Yale School of Medicine), Giorgio Scagliotti, MD, PhD (University of Torino).

ALCF and VAPF are proud to announce the recipients of the 2014 YITA who truly embody the multidisciplinary, translational and cross-institutional spirit of the award- the translational and clinical strengths as well as tumor molecular profiling and clinical specimen resources contributed by Dr. Riess and Dr. Corcoran will synergize with the biological investigations executed by Dr. Bivona.

These novel studies hold the potential to impact the lives of not only lung cancer patients, but also those of patients with melanoma, pancreatic, thyroid and colon cancer in which this signaling pathway plays a crucial role in tumor growth and therapy resistance.

First Progress Report, May 2015

Activating mutations in RAS and BRAF occur in many human tumors, including non-small cell lung cancer (NSCLC). RAF and MEK inhibitors have been used in patients with RAS and BRAF mutant tumors including NSCLC, but resistance remains a major clinical challenge. Indeed, RAF or MEK inhibitors are initially but only transiently effective in some but not all BRAF mutant patients, and are largely ineffective in RAS mutant patients because of resistance. Thus, the identification of novel therapy strategies is a critical unmet need to improve patient survival. To address this challenge, we conducted a synthetic lethal genetic screen in BRAF mutant NSCLC cells and discovered that the Hippo pathway effector YAP (and its paralog TAZ) broadly promotes resistance to RAF or MEK inhibitor therapy not only in BRAF but also RAS mutant NSCLC (Lin L. et al., Nature Genetics 2015). Our findings uncover a promising synthetic lethal approach targeting both YAP and RAF-MEK to enhance patient survival. Moreover, additional patient tumor profiling studies revealed YAP1 or TAZ focal genomic amplification in ~20% of NSCLCs, including some EGFR mutant and ALK fusion positive NSCLCs with acquired resistance to EGFR or ALK kinase inhibitors. Hence, YAP/TAZ may be a critical target in NSCLC patients more broadly, including those with “druggable” targets (e.g. mutant BRAF), those with intractable targets (e.g. mutant RAS), and those with YAP/TAZ amplification that lack other targets. We will explore the hypothesis that YAP/TAZ activation promotes tumor survival and therapy resistance in NSCLC in an innovative, multidisciplinary project with potential immediate and high clinical impact.

Our project aims to improve the survival of lung cancer patients by enhancing their precision treatment. We aim to capitalize on our exciting recent discovery of Hippo- YAP signaling as an important biological circuit and therapeutic target in several lethal human cancers, including lung, colon, thyroid, pancreas, and melanoma. The Hippo- YAP pathway emerged in our preliminary studies in which we used discovered that its activation causes resistance to therapy in certain lung cancers with RAS and BRAF mutations. We found that blocking YAP signaling enhanced response and overcame treatment resistance in these lung cancers. We also found that members of this pathway (YAP and TAZ) are might promote the growth of additional subsets of lung cancer because these genes are amplified in ~20% of lung tumors.

During the initial project period, we have made exciting progress toward understanding and targeting the YAP signaling pathway to combat tumor growth and therapy resistance. We have discovered that this pathway controls therapy response by regulating certain cell death proteins, that blocking YAP with a drug called verteporfin may be an effective new treatment strategy against several types of lung cancer cells, and that YAP is increased in primary patient tumors. Our multidisciplinary team of innovators has gained substantial momentum during the initial project period – forward progress that we believe will continue to provide important new insights into the role and relevance of targeting YAP signaling to improve the survival of multiple molecular classes of lung cancer patients.

We are collecting paired patient samples of important histologic (squamous and adenocarcinoma) and molecular subtypes (such as EGFR, ALK, KRAS and BRAF) for analysis for YAP1 and TAZ IHC and FISH across institutions (UCSF, UC Davis, MGH). We have created a database to capture relevant clinical and pathologic data to correlate with YAP1/TAZ expression.

We have incorporated analysis of YAP1 and TAZ IHC and FISH tissue correlates into prospective clinical trial protocols developed across important molecular subtypes including:

  • A Phase I trial of AZD9291 and Necitumumab in EGFR-mutant NSCLC with Progression on Prior EGFR-TKI (PI: JW Riess, NCI sponsored).
  • A Phase I/II Trial of Afatinib and Ganetespib with a Focus on EGFR-mutant NSCLC (JW Riess, PI, UC Davis).
  • A Phase I/II Trial of Ceritinib and Trametinib in ALK Rearranged NSCLC (C. Blakely PI and JW Riess co-PI, UCSF and UC Davis).
  • A Phase II Trial of Docetaxel and Trametinib in KRAS Mutant NSCLC (PI: S. Gadjeel, Co-PI JW Riess, SWOG and NCI).
  • We will analyze samples from existing relevant clinical trials including NSCLC lung cancer patients enrolled in a Trial of Trametinib and Navitoclax in Advanced KRAS mutant Solid Tumors.