K-Ras associates with the plasma membrane (PM) through farnesylation that functions in conjunction with an adjacent polybasic sequence. We show that phosphorylation by protein kinase C (PKC) of S181 within the polybasic region promotes rapid dissociation of K-Ras from the PM and association with intracellular membranes, including the outer membrane of mitochondria where phospho-K-Ras interacts with Bcl-XL. PKC agonists promote apoptosis of cells transformed with oncogenic K-Ras in a S181-dependent manner. K-Ras with a phosphomimetic residue at position 181 induces apoptosis via a pathway that requires Bcl-XL. The PKC agonist bryostatin-1 inhibited the growth in vitro and in vivo of cells transformed with oncogenic K-Ras in a S181-dependent fashion. These data demonstrate that the location and function of K-Ras are regulated directly by PKC and suggest an approach to therapy of K-Ras-dependent tumors with agents that stimulate phosphorylation of S181.

The authors propose a new theoretical rationale that explains the paired existence of both a manufacturer's decision to limit the number of intermediaries operating in a specific geographic market and a distributor's decision to limit brand assortment in a product category. Using transaction cost reasoning, they suggest that channel selectivity agreements can be understood as interrelated exchanges of pledges, or credible commitments, that counterbalance exposure to opportunism and neutralize sources of relationship instability, thereby strengthening an interorganizational relationship. The empirical results, which are based on dyadic data from 362 manufacturer–distributor relationships, are broadly supportive of their framework.

The objective of this study is to estimate the effectiveness of different defense strategies when faced with a new product introduction by a competitor. Using a sample of in cumbentsacross a wide range of industries, we find that faster reactions to the new entrant have a positive impact on the perceived success of the defense strategy. However, the greater the breadth of reaction (number of marketing mix instruments used), the less successful is the defense. The ability of an incumbent to maintain its market position is also significantly affected by industry characteristics and the degree of competitive threat posed by the new product entry. A working paper in the INSEAD Working Paper Sertes is intended as a means whereby a faculty researcher's thoughts and findings may be communicated to interested readers. The paper should be considered preliminary in nature and may require révision. INCOMBENT DEFENSE STRATEGIES AGAINST NEW PRODUCT ENTRY AbstractThe objective of this study is to estimate the effectiveness of different defense strategies when faced with a new product introduction by a competitor. Using a sample of incumbents across a wide range of industries, we find that faster reactions to the new entrant have a positive impact on the perceived success of the defense strategy. However, the greater the breadth of reaction (number of marketing mix instruments used), the less successful the defense. The ability of an incumbent to maintain its market position is also significantly affected by industry characteristics and the degree of competitive threat posed by the entrant. INCOMBENT DEFENSE STRATEGIES AGAINST NEW PRODUCT ENTRYThe focus of this research is on the defense strategies that incumbents use when confronted with new competitive products. The goal is to explain the success of reaction strategies, radier than to explain the likelihood of reaction, which is the more prevalent research objective in the extant literature. In other words our concem is not with whether incumbents react, but given that they react, how successful will their responses be? In particular, are faster responses likely to be more successful? Which marketing instruments should be used? Are broad responses (in ternis of number of marketing mix instruments) more successful than narrow responses?The issue of market defense has considerable managerial relevance. In general, as the success of incumbents increases within a product category, the likelihood of new entry increases and with it the need for incumbents to defend their position. In many firms, however, the bias is to develop elaborate new product launch plans but seldom to proactively specify defense plans in advance of a competitive threat (Bazerman and Carroll 1987, Robertson and Gatignon 1991).The bottom line question for managers is what defense strategies will be most effective. More specifically, the question is what responses will be most successful given a certain set of procluct category characteristics and the nature of the competitive threat. It is these mana...

Oral prescription drugs are an increasingly important treatment option for cancer. Yet contemporaneous US trends in spending on anticancer drugs known as oral oncologics have not been described. Using nationally representative data, we describe trends in national spending on and use of forty-seven oral oncologics between the first quarter of 2006 and the third quarter of 2011. Average quarterly national spending on oral oncologics increased 37 percent, from $940.3 million to $1.4 billion in 2012 dollars, a significant change. Average quarterly use of oral oncologics in the same time period measured in extended units increased at a significant pace but more slowly than spending (10 percent). Within this broader trend, differences in spending among categories of oral oncologics were observed. High levels of and increases in both spending and use were concentrated among new brand-name and patent-protected oral oncologics, including second-generation tyrosine kinase inhibitors used to treat chronic myelogenous leukemia. Decreased spending but increased use was observed among oral oncologics that lost patent protection during the study period and were available in generic form, including hormonal therapies used to treat breast and prostate cancers. Spending on new and patent-protected oral oncologics and associated price increases are significant drivers of increased spending.

Shakeouts loom large in the landscape of all fast-growing markets. During the boom period, an unsustainable glut of competitors is attracted by forecasts of high growth and promises of exceptional returns. Even when the market is already crowded, more entrants keep arriving. These followers are often naïve about the barriers to entry and don't realize how many others are also poised to enter at the same time. Reality intrudes with a bust that precipitates the exit of more than 80 percent of the players through failure or acquisition. This shakeout is triggered by some combination of disappointing growth, pricing pressures that degrade profit prospects, or shortages of crucial people and financial resources. Disciplines